SemOpenAlex |

SemOpenAlex

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2077490693> ?p ?o ?g. }

Showing items 1 to 100 of ±128 with 100 items per page.

W2077490693 endingPage "10052" @default.
W2077490693 startingPage "10047" @default.
W2077490693 abstract "As part of a program to further understand the mechanism by which extracellular signals are coordinated and cell-specific outcomes are generated, we have cloned a novel class of related adaptor molecules (NSP1, NSP2, and NSP3) and have characterized in more detail one of the members, NSP1. NSP1 has an Shc-related SH2 domain and a putative proline/serine-rich SH3 interaction domain. Treatment of cells with epidermal growth factor or insulin leads to NSP1 phosphorylation and increased association with a hypophosphorylated adaptor protein, p130Cas. In contrast, cell contact with fibronectin results in Cas phosphorylation and a transient dissociation of NSP1 from p130Cas. Increased expression of NSP1 in 293 cells induces activation of JNK1, but not of ERK2. Consistent with this observation, NSP1 increases the activity of an AP-1-containing promoter. Thus, we have described a novel family of adaptor proteins, one of which may be involved in the process by which receptor tyrosine kinase and integrin receptors control the c-Jun N-terminal kinase/stress-activated protein kinase pathway. As part of a program to further understand the mechanism by which extracellular signals are coordinated and cell-specific outcomes are generated, we have cloned a novel class of related adaptor molecules (NSP1, NSP2, and NSP3) and have characterized in more detail one of the members, NSP1. NSP1 has an Shc-related SH2 domain and a putative proline/serine-rich SH3 interaction domain. Treatment of cells with epidermal growth factor or insulin leads to NSP1 phosphorylation and increased association with a hypophosphorylated adaptor protein, p130Cas. In contrast, cell contact with fibronectin results in Cas phosphorylation and a transient dissociation of NSP1 from p130Cas. Increased expression of NSP1 in 293 cells induces activation of JNK1, but not of ERK2. Consistent with this observation, NSP1 increases the activity of an AP-1-containing promoter. Thus, we have described a novel family of adaptor proteins, one of which may be involved in the process by which receptor tyrosine kinase and integrin receptors control the c-Jun N-terminal kinase/stress-activated protein kinase pathway. mitogen-activated protein kinase extracellular signal-regulated kinase MAPK/ERK kinase kinase c-Jun N-terminal kinase epidermal growth factor focal adhesion kinase expressed sequence tag Chinese hamster ovary serum response element Cell contact with growth factors and extracellular matrix activates one or more of the MAPK1 pathways, and these responses appear to be critical for the appropriate regulation of cell division and differentiation (1Madhani H.D. Fink G.R. Trends Genet. 1998; 14: 151-155Abstract Full Text Full Text PDF PubMed Scopus (233) Google Scholar, 2Seger R. Krebs E.G. FASEB J. 1995; 9: 726-735Crossref PubMed Scopus (3187) Google Scholar). Although many of the molecules that participate in these processes have been defined, there are still significant gaps in our understanding of how multiple signals are integrated into an appropriate outcome.The MAPK kinase family of proteins (ERK, JNK, and p38) can phosphorylate and activate one or more transcription factors and are activated by a cascade of upstream kinases (for reviews, see Refs. 3Waskiewicz A.J. Cooper J.A. Current Opinion in Cell Biology. 1995; 7: 798-805Crossref PubMed Scopus (534) Google Scholarand 4Treisman R. Curr. Opin. Cell Biol. 1996; 8: 205-215Crossref PubMed Scopus (1160) Google Scholar). The JNK series of kinases that are part of the process that leads to the activation of AP-1-containing promoters (6Karin M. Liu Z. Zandi E. Curr. Opin. Cell Biol. 1997; 9: 240-246Crossref PubMed Scopus (2280) Google Scholar) appear to be especially critical for transducing an immediate response to a changing environment and for regulating cell proliferation (5Ip Y.T. Davis R.J. Curr. Opin. Cell Biol. 1998; 10: 205-219Crossref PubMed Scopus (1374) Google Scholar). JNK is itself activated following phosphorylation by a JNK kinase (7Lin A. Minden A. Martinetto H. Claret F.X. Lange-Carter C. Mercurio F. Johnson G.L. Karin M. Science. 1995; 268: 286-290Crossref PubMed Scopus (706) Google Scholar, 8Yan M. Dai T. Deak J.C. Kyriakis J.M. Zon L.I. Woodgett J.R. Templeton D.J. Nature. 1994; 372: 798-800Crossref PubMed Scopus (658) Google Scholar, 9Sanchez I. Hughes R.T. Mayer B.J. Yee K. Woodgett J.R. Avruch J. Kyriakis J.M. Zon L.I. Nature. 1994; 372: 794-798Crossref PubMed Scopus (913) Google Scholar, 10Derijard B. Raingeaud J. Barrett T. Wu I.H. Han J. Ulevitch R.J. Davis R.J. Science. 1995; 267: 682-685Crossref PubMed Scopus (1405) Google Scholar), which in turn is also activated by phosphorylation. Although several kinases have been described that can phosphorylate the JNK kinases, the most important appear to be the MEKK proteins (11Minden A. Lin A. McMahon M. Lange-Carter C. Derijard B. Davis R.J. Johnson G.L. Karin M. Science. 1994; 266: 1719-1723Crossref PubMed Scopus (1010) Google Scholar). Activation of the MEKK proteins is dependent on one or more of the small GTP-binding proteins such as Cdc42, Rac, and Ras (12Coso O.A. Chiariello M. Yu J.C. Teramoto H. Crespo P. Xu N. Miki T. Gutkind J.S. Cell. 1995; 81: 1137-1146Abstract Full Text PDF PubMed Scopus (1559) Google Scholar, 13Collins L.R. Minden A. Karin M. Brown J.H. J. of Biological Chemistry. 1996; 271: 17349-17353Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar, 14Minden A. Lin A. Claret F.X. Abo A. Karin M. Cell. 1995; 81: 1147-1157Abstract Full Text PDF PubMed Scopus (1444) Google Scholar). Although the activation of the MAPK kinases can be described in terms of a linear series of sequential activations, it has become clear that many of the relevant components are assembled into complexes through scaffolding molecules such as MP1 (15Schaeffer H.J. Catling A.D. Eblen S.T. Collier L.S. Krauss A. Weber M.J. Science. 1998; 281: 1668-1671Crossref PubMed Scopus (384) Google Scholar) and JIP-1 (16Whitmarsh A.J. Cavanagh J. Tournier C. Yasuda J. Davis R.J. Science. 1998; 281: 1671-1674Crossref PubMed Scopus (583) Google Scholar).Growth factors such as EGF can stimulate all of the MAPK kinases (11Minden A. Lin A. McMahon M. Lange-Carter C. Derijard B. Davis R.J. Johnson G.L. Karin M. Science. 1994; 266: 1719-1723Crossref PubMed Scopus (1010) Google Scholar), and for the ERK kinases, many of the components of the pathway are well established (17Sugden P.H. Clerk A. Cell. Signalling. 1997; 9: 337-351Crossref PubMed Scopus (282) Google Scholar). In contrast, the signaling from EGF to the JNK pathway has received relatively less attention. The ability of EGF to activate guanylate exchange factors such as Sos and the known involvement of the GTP-binding proteins in JNK activation suggest that EGF may also be linked to JNK via guanylate exchange factors (18Clarke N. Arenzana N. Hai T. Minden A. Prywes R. Mol. Cell. Biol. 1998; 18: 1065-1073Crossref PubMed Scopus (95) Google Scholar). A role for phosphatidylinositol 3-kinase in linking EGF to JNK has also been reported (19Logan S.K. Falasca M. Hu P. Schlessinger J. Mol. Cell. Biol. 1997; 17: 5784-5790Crossref PubMed Scopus (123) Google Scholar).The immediate outcome of integrin receptor activation is the formation of a large complex of kinases and adaptor proteins. This complex contains at least the kinases FAK, c-Crk, and c-Src and the adaptor molecule Cas (Crk-associatedsubstrate) (20Polte T.R. Hanks S.K. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 10678-10682Crossref PubMed Scopus (386) Google Scholar, 21Hanks S.K. Polte T.R. Bioessays. 1997; 19: 137-145Crossref PubMed Scopus (440) Google Scholar, 22Harte M.T. Hildebrand J.D. Burnham M.R. Bouton A.H. Parsons J.T. J. Biol. Chem. 1996; 271: 13649-13655Abstract Full Text Full Text PDF PubMed Scopus (322) Google Scholar). FAK is primarily responsible for phosphorylating a number of proteins involved in cytoskeletal assembly (23Leventhal P.S. Shelden E.A. Kim B. Feldman E.L. J. Biol. Chem. 1997; 272: 5214-5218Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar, 24Schaller M.D. Parsons J.T. Mol. Cell. Biol. 1995; 15: 1645-2635Crossref Scopus (499) Google Scholar), whereas c-Src (or Src-like kinases) can phosphorylate Cas (25Hamasaki K. Mimura T. Morino N. Furuya H. Nakamoto T. Aizawa S. Morimoto C. Yazaki Y. Hirai H. Nojima Y. Biochem. Biophys. Res. Commun. 1996; 222: 338-343Crossref PubMed Scopus (116) Google Scholar) and can activate the MAPK pathway (26Macdonald S.G. Crews C.M. Wu L. Driller J. Clark R. Erikson R.L. McCormick F. Mol. Cell. Biol. 1993; 13: 6615-6620Crossref PubMed Scopus (202) Google Scholar, 27Gardner A.M. Vaillancourt R.R. Johnson G.L. J. Biol. Chem. 1993; 268: 17896-18901Abstract Full Text PDF PubMed Google Scholar). Cas, originally identified as a hyperphosphorylated protein following induced expression of the viral oncogene Crk (v-Crk) (28Sakai R. Iwamatsu A. Hirano N. Ogawa S. Tanaka T. Mano H. Yazaki Y. Hirai H. EMBO J. 1994; 13: 3748-3756Crossref PubMed Scopus (592) Google Scholar), is phosphorylated in response to growth factors acting through receptor tyrosine kinases (29Casamassima A. Rozengurt E. J. Biol. Chem. 1997; 272: 9363-9370Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar) and integrin-mediated signaling (30Nojima Y. Morino N. Mimura T. Hamasaki K. Furuya H. Sakai R. Sato T. Tachibana K. Morimoto C. Yazaki Y. Hirai H. J. Biol. Chem. 1995; 270: 15398-15402Crossref PubMed Scopus (292) Google Scholar). As Cas has an SH3-domain as well as multiple SH2-binding motifs, Cas may well assemble a number of proteins such as FAK (20Polte T.R. Hanks S.K. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 10678-10682Crossref PubMed Scopus (386) Google Scholar) and the phosphatases PTP-PEST (31Garton A.J. Flint A.J. Tonks N.K. Mol. Cell. Biol. 1996; 16: 6408-6418Crossref PubMed Scopus (231) Google Scholar) and PTP1B (32Liu F. Hill D.E. Chernoff J. J. Biol. Chem. 1996; 271: 31290-31295Abstract Full Text Full Text PDF PubMed Scopus (204) Google Scholar) into a single complex. Cas may be a critical component by which extracellular events influence cell morphology and survival (33Daniel J.M. Reynolds A.B. Mol. Cell. Biol. 1995; 15: 4819-4824Crossref PubMed Google Scholar, 34Mo Y.Y. Reynolds A.B. Cancer Res. 1996; 56: 2633-2640PubMed Google Scholar, 35Nakamoto T. Sakai R. Honda H. Ogawa S. Ueno H. Suzuki T. Aizawa S. Yazaki Y. Hirai H. Mol. Cell. Biol. 1997; 17: 3884-3897Crossref PubMed Scopus (135) Google Scholar).A theme running through the mechanism by which transcription factors such as AP-1 are activated by receptor tyrosine kinases and integrin receptors is the importance of adaptor proteins. These adaptor proteins contain one or multiple domains that mediate protein-protein or protein-lipid interactions (for review, see Ref. 36Pawson T. Scott J.D. Science. 1997; 278: 2075-2080Crossref PubMed Scopus (1887) Google Scholar). In addition to integrating independent extracellular signals, cell type-specific expression of the adaptor molecules may be critical in determining the cell type-specific response to extracellular stimuli. Although most of the more extensively characterized signal transduction molecules are ubiquitously expressed (15Schaeffer H.J. Catling A.D. Eblen S.T. Collier L.S. Krauss A. Weber M.J. Science. 1998; 281: 1668-1671Crossref PubMed Scopus (384) Google Scholar, 37Nakamura T. Sanokawa R. Sasaki Y. Ayusawa D. Oishi M. Mori N. Oncogene. 1996; 13: 1111-1121PubMed Google Scholar, 38Sun X.J. Pons S. Wang L.M. Zhang Y. Yenush L. Burks D. Myers Jr., M.G. Glasheen E. Copeland N.G. Jenkins N.A. Pierce J.H. White M.F. Mol. Endocrinol. 1997; 11: 251-262Crossref PubMed Scopus (123) Google Scholar), a few adaptor molecules with a limited pattern of expression have been identified, such as N-Shc (37Nakamura T. Sanokawa R. Sasaki Y. Ayusawa D. Oishi M. Mori N. Oncogene. 1996; 13: 1111-1121PubMed Google Scholar) and Grb-IR (39Liu F. Roth R.A. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 10287-10291Crossref PubMed Scopus (150) Google Scholar).To identify additional adaptor proteins that are involved in growth factor and integrin signaling, we have searched an expressed sequence tag (EST) data base for sequences that share homology with SH2-containing adaptor proteins. By this method, we isolated a cDNA encoding a family of novel SH2-containing proteins. The structure and characteristics of at least NSP1 (novelSH2-containing protein 1) suggest that this protein may play an important role in cell proliferation and fetal development.DISCUSSIONWe have isolated a family of novel adaptor proteins (NSP1, NSP2, and NSP3) that contain an N-terminal SH2 domain, a central proline/serine-rich region, and a C-terminal sequence that is distinctive for the NSP proteins. While this manuscript was in preparation, the sequence of NSP2 was published as BCAR3; this protein (BCAR3) appears to be implicated in the development of resistance to the cytostatic agent Taxol (40van Agthoven T. van Agthoven T.L. Dekker A. van der Spek P.J. Vreede L. Dorssers L.C. EMBO J. 1998; 17: 2799-2808Crossref PubMed Scopus (96) Google Scholar). NSP1expression may be restricted to tissues with secretory epithelial cells, whereas NSP2 and NSP3 are expressed in variety of tissues. In hematopoietic tissues, twoNSP3-related transcripts are detected. The coding potential of these two NSP3 transcripts is being explored.NSP1 is phosphorylated in response to insulin and EGF (and insulin-like growth factor I and heregulin (data not shown)), indicating that NSP1 is a common target for a variety of growth factor receptors. In response to EGF, NSP1 associates with the EGF receptor and is phosphorylated. The data are consistent with a direct interaction between the phosphotyrosines on the EGF receptor and the NSP1 SH2 domain and a subsequent receptor kinase-dependent phosphorylation of NSP1. Preliminary data indicate that the SH2 domain alone is able to interact with the EGF receptor, although other regions of NSP1 may also participate in this interaction (data not shown). It is also possible that the EGF receptor-NSP1 interaction is indirect. NSP1 is only modestly phosphorylated in response to integrin signaling. This weak integrin-mediated phosphorylation could conceivably be through FAK or Src-related kinases, both of which are known to associate with Cas (20Polte T.R. Hanks S.K. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 10678-10682Crossref PubMed Scopus (386) Google Scholar, 22Harte M.T. Hildebrand J.D. Burnham M.R. Bouton A.H. Parsons J.T. J. Biol. Chem. 1996; 271: 13649-13655Abstract Full Text Full Text PDF PubMed Scopus (322) Google Scholar, 25Hamasaki K. Mimura T. Morino N. Furuya H. Nakamoto T. Aizawa S. Morimoto C. Yazaki Y. Hirai H. Nojima Y. Biochem. Biophys. Res. Commun. 1996; 222: 338-343Crossref PubMed Scopus (116) Google Scholar, 28Sakai R. Iwamatsu A. Hirano N. Ogawa S. Tanaka T. Mano H. Yazaki Y. Hirai H. EMBO J. 1994; 13: 3748-3756Crossref PubMed Scopus (592) Google Scholar, 41Astier A. Manie S.N. Avraham H. Hirai H. Law S.F. Zhang Y. Golemis E.A. Fu Y. Druker B.J. Haghayeghi N. Freedman A.S. Avraham S. J. Biol. Chem. 1997; 272: 19719-19724Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar).Co-immunoprecipitation experiments revealed that NSP1 interacts with p130Cas. Preliminary data from a yeast two-hybrid analysis are consistent with this result and suggest that the interaction is direct (data not shown). In the co-immunoprecipitation experiments, the interaction between NSP1 and Cas could be detected under conditions in which there was no detectable phosphorylation of NSP1 or Cas, suggesting that the interaction between NSP1 and Cas is phosphorylation-independent and may occur via the SH3 domain in Cas and the proline/serine-rich domain in NSP1. Neither of the demonstrated associations (EGF receptor and Cas) appears to utilize the phosphotyrosines in NSP1. This conclusion is reinforced by the experiments using the tyrosine replacement variants in which both EGF receptor and Cas interactions can occur in the absence of any detectable NSP1 phosphorylation.The relative level of the NSP1·Cas complex and the phosphorylation status of Cas are quite different between receptor tyrosine kinase and integrin signaling. Thus, EGF treatment leads to NSP1 phosphorylation, to dephosphorylation of the Cas that is associated with NSP1, and to an increase in the amount of the NSP·Cas complex. In contrast, in response to fibronectin, there is little change in NSP1 phosphorylation, but there is a significant increase in the phosphorylation of the Cas associated with NSP1. Cas dephosphorylation in response to EGF (42Ojaniemi M. Vuori K. J. Biol. Chem. 1997; 272: 25993-25998Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar) and Cas phosphorylation in response to fibronectin (30Nojima Y. Morino N. Mimura T. Hamasaki K. Furuya H. Sakai R. Sato T. Tachibana K. Morimoto C. Yazaki Y. Hirai H. J. Biol. Chem. 1995; 270: 15398-15402Crossref PubMed Scopus (292) Google Scholar, 43Manie S.N. Astier A. Haghayeghi N. Canty T. Druker B.J. Hirai H. Freedman A.S. J. Biol. Chem. 1997; 272: 15636-15641Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar, 44Vuori K. Hirai H. Aizawa S. Ruoslahti E. Mol. Cell. Biol. 1996; 16: 2606-2613Crossref PubMed Google Scholar) have been previously reported. There is also an apparent dissociation of NSP1 from Cas at short time periods and a subsequent reassociation at longer (4 h) times. These results led to the hypothesis that the biological outcome in response to extracellular signals could be quite distinct in the presence or absence of NSP1. For example, FAK associates with the SH3 region in Cas via a PXXP region at the C terminus of FAK (P715SRP; mouse nomenclature (22Harte M.T. Hildebrand J.D. Burnham M.R. Bouton A.H. Parsons J.T. J. Biol. Chem. 1996; 271: 13649-13655Abstract Full Text Full Text PDF PubMed Scopus (322) Google Scholar)). There are six PXXP signatures in NSP1. Thus, it is possible that NSP1 could compete for the SH3 region in Cas and decrease the amount of FAK that is bound to Cas and so alter FAK-dependent events (21Hanks S.K. Polte T.R. Bioessays. 1997; 19: 137-145Crossref PubMed Scopus (440) Google Scholar). In contrast, EGF treatment leads to NSP1 phosphorylation, to dephosphorylation of NSP1-associated Cas, and to an increase in the amount of the NSP1·Cas complex. This complex is then likely to have a decrease in the number of proteins associated with the phosphotyrosines in Cas and so may lead to changes in downstream signaling.Increased expression of NSP1 results in JNK activation and increased expression from an AP-1-dependent promoter. Whether this activation of JNK is related to the EGF-stimulated phosphorylation of NSP1 or the interaction of Cas with NSP1 is currently unknown, although preliminary data from a luciferase assay indicate that NSP1Y95F, which is not phosphorylated but still interacts with both Cas and the EGF receptor, has diminished but not abolished activity in this assay. It has been previously shown that activation of the JNK kinase cascade is dependent on one of several small GTP-binding proteins (Cdc42, Rac, and Ras) (12Coso O.A. Chiariello M. Yu J.C. Teramoto H. Crespo P. Xu N. Miki T. Gutkind J.S. Cell. 1995; 81: 1137-1146Abstract Full Text PDF PubMed Scopus (1559) Google Scholar, 14Minden A. Lin A. Claret F.X. Abo A. Karin M. Cell. 1995; 81: 1147-1157Abstract Full Text PDF PubMed Scopus (1444) Google Scholar) and on phosphatidylinositol 3-kinase (19Logan S.K. Falasca M. Hu P. Schlessinger J. Mol. Cell. Biol. 1997; 17: 5784-5790Crossref PubMed Scopus (123) Google Scholar). How or whether NSP1 can modify any of these components of the signaling pathway is under investigation.The activation of the c-Jun kinases in response to receptor tyrosine kinase and integrin receptor signaling appears to be critical for regulating cell proliferation (45Antonyak M.A. Moscatello D.K. Wong A.J. J. Biol. Chem. 1998; 273: 2817-2822Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar, 46Bost F. McKay R. Dean N. Mercola D. J. Biol. Chem. 1997; 272: 33422-33429Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar, 47Auer K.L. Contessa J. Brenz-Verca S. Pirola L. Rusconi S. Cooper G. Abo A. Wymann M.P. Davis R.J. Birrer M. Dent P. Mol. Biol. Cell. 1998; 9: 561-573Crossref PubMed Scopus (114) Google Scholar). Furthermore, genetic analysis of JNK signaling in Drosophila (5Ip Y.T. Davis R.J. Curr. Opin. Cell Biol. 1998; 10: 205-219Crossref PubMed Scopus (1374) Google Scholar) and the abnormal liver development in mice genetically lacking the JNK kinase activator MKK4 suggest a critical role for JNK in normal development (48Yang D. Tournier C. Wysk M. Lu H.T. Xu J. Davis R.J. Flavell R.A. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 3004-3009Crossref PubMed Scopus (258) Google Scholar). Thus, the identification of a novel adaptor protein that functions in these processes may provide a valuable molecular tool for understanding cell proliferation and fetal development. Cell contact with growth factors and extracellular matrix activates one or more of the MAPK1 pathways, and these responses appear to be critical for the appropriate regulation of cell division and differentiation (1Madhani H.D. Fink G.R. Trends Genet. 1998; 14: 151-155Abstract Full Text Full Text PDF PubMed Scopus (233) Google Scholar, 2Seger R. Krebs E.G. FASEB J. 1995; 9: 726-735Crossref PubMed Scopus (3187) Google Scholar). Although many of the molecules that participate in these processes have been defined, there are still significant gaps in our understanding of how multiple signals are integrated into an appropriate outcome. The MAPK kinase family of proteins (ERK, JNK, and p38) can phosphorylate and activate one or more transcription factors and are activated by a cascade of upstream kinases (for reviews, see Refs. 3Waskiewicz A.J. Cooper J.A. Current Opinion in Cell Biology. 1995; 7: 798-805Crossref PubMed Scopus (534) Google Scholarand 4Treisman R. Curr. Opin. Cell Biol. 1996; 8: 205-215Crossref PubMed Scopus (1160) Google Scholar). The JNK series of kinases that are part of the process that leads to the activation of AP-1-containing promoters (6Karin M. Liu Z. Zandi E. Curr. Opin. Cell Biol. 1997; 9: 240-246Crossref PubMed Scopus (2280) Google Scholar) appear to be especially critical for transducing an immediate response to a changing environment and for regulating cell proliferation (5Ip Y.T. Davis R.J. Curr. Opin. Cell Biol. 1998; 10: 205-219Crossref PubMed Scopus (1374) Google Scholar). JNK is itself activated following phosphorylation by a JNK kinase (7Lin A. Minden A. Martinetto H. Claret F.X. Lange-Carter C. Mercurio F. Johnson G.L. Karin M. Science. 1995; 268: 286-290Crossref PubMed Scopus (706) Google Scholar, 8Yan M. Dai T. Deak J.C. Kyriakis J.M. Zon L.I. Woodgett J.R. Templeton D.J. Nature. 1994; 372: 798-800Crossref PubMed Scopus (658) Google Scholar, 9Sanchez I. Hughes R.T. Mayer B.J. Yee K. Woodgett J.R. Avruch J. Kyriakis J.M. Zon L.I. Nature. 1994; 372: 794-798Crossref PubMed Scopus (913) Google Scholar, 10Derijard B. Raingeaud J. Barrett T. Wu I.H. Han J. Ulevitch R.J. Davis R.J. Science. 1995; 267: 682-685Crossref PubMed Scopus (1405) Google Scholar), which in turn is also activated by phosphorylation. Although several kinases have been described that can phosphorylate the JNK kinases, the most important appear to be the MEKK proteins (11Minden A. Lin A. McMahon M. Lange-Carter C. Derijard B. Davis R.J. Johnson G.L. Karin M. Science. 1994; 266: 1719-1723Crossref PubMed Scopus (1010) Google Scholar). Activation of the MEKK proteins is dependent on one or more of the small GTP-binding proteins such as Cdc42, Rac, and Ras (12Coso O.A. Chiariello M. Yu J.C. Teramoto H. Crespo P. Xu N. Miki T. Gutkind J.S. Cell. 1995; 81: 1137-1146Abstract Full Text PDF PubMed Scopus (1559) Google Scholar, 13Collins L.R. Minden A. Karin M. Brown J.H. J. of Biological Chemistry. 1996; 271: 17349-17353Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar, 14Minden A. Lin A. Claret F.X. Abo A. Karin M. Cell. 1995; 81: 1147-1157Abstract Full Text PDF PubMed Scopus (1444) Google Scholar). Although the activation of the MAPK kinases can be described in terms of a linear series of sequential activations, it has become clear that many of the relevant components are assembled into complexes through scaffolding molecules such as MP1 (15Schaeffer H.J. Catling A.D. Eblen S.T. Collier L.S. Krauss A. Weber M.J. Science. 1998; 281: 1668-1671Crossref PubMed Scopus (384) Google Scholar) and JIP-1 (16Whitmarsh A.J. Cavanagh J. Tournier C. Yasuda J. Davis R.J. Science. 1998; 281: 1671-1674Crossref PubMed Scopus (583) Google Scholar). Growth factors such as EGF can stimulate all of the MAPK kinases (11Minden A. Lin A. McMahon M. Lange-Carter C. Derijard B. Davis R.J. Johnson G.L. Karin M. Science. 1994; 266: 1719-1723Crossref PubMed Scopus (1010) Google Scholar), and for the ERK kinases, many of the components of the pathway are well established (17Sugden P.H. Clerk A. Cell. Signalling. 1997; 9: 337-351Crossref PubMed Scopus (282) Google Scholar). In contrast, the signaling from EGF to the JNK pathway has received relatively less attention. The ability of EGF to activate guanylate exchange factors such as Sos and the known involvement of the GTP-binding proteins in JNK activation suggest that EGF may also be linked to JNK via guanylate exchange factors (18Clarke N. Arenzana N. Hai T. Minden A. Prywes R. Mol. Cell. Biol. 1998; 18: 1065-1073Crossref PubMed Scopus (95) Google Scholar). A role for phosphatidylinositol 3-kinase in linking EGF to JNK has also been reported (19Logan S.K. Falasca M. Hu P. Schlessinger J. Mol. Cell. Biol. 1997; 17: 5784-5790Crossref PubMed Scopus (123) Google Scholar). The immediate outcome of integrin receptor activation is the formation of a large complex of kinases and adaptor proteins. This complex contains at least the kinases FAK, c-Crk, and c-Src and the adaptor molecule Cas (Crk-associatedsubstrate) (20Polte T.R. Hanks S.K. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 10678-10682Crossref PubMed Scopus (386) Google Scholar, 21Hanks S.K. Polte T.R. Bioessays. 1997; 19: 137-145Crossref PubMed Scopus (440) Google Scholar, 22Harte M.T. Hildebrand J.D. Burnham M.R. Bouton A.H. Parsons J.T. J. Biol. Chem. 1996; 271: 13649-13655Abstract Full Text Full Text PDF PubMed Scopus (322) Google Scholar). FAK is primarily responsible for phosphorylating a number of proteins involved in cytoskeletal assembly (23Leventhal P.S. Shelden E.A. Kim B. Feldman E.L. J. Biol. Chem. 1997; 272: 5214-5218Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar, 24Schaller M.D. Parsons J.T. Mol. Cell. Biol. 1995; 15: 1645-2635Crossref Scopus (499) Google Scholar), whereas c-Src (or Src-like kinases) can phosphorylate Cas (25Hamasaki K. Mimura T. Morino N. Furuya H. Nakamoto T. Aizawa S. Morimoto C. Yazaki Y. Hirai H. Nojima Y. Biochem. Biophys. Res. Commun. 1996; 222: 338-343Crossref PubMed Scopus (116) Google Scholar) and can activate the MAPK pathway (26Macdonald S.G. Crews C.M. Wu L. Driller J. Clark R. Erikson R.L. McCormick F. Mol. Cell. Biol. 1993; 13: 6615-6620Crossref PubMed Scopus (202) Google Scholar, 27Gardner A.M. Vaillancourt R.R. Johnson G.L. J. Biol. Chem. 1993; 268: 17896-18901Abstract Full Text PDF PubMed Google Scholar). Cas, originally identified as a hyperphosphorylated protein following induced expression of the viral oncogene Crk (v-Crk) (28Sakai R. Iwamatsu A. Hirano N. Ogawa S. Tanaka T. Mano H. Yazaki Y. Hirai H. EMBO J. 1994; 13: 3748-3756Crossref PubMed Scopus (592) Google Scholar), is phosphorylated in response to growth factors acting through receptor tyrosine kinases (29Casamassima A. Rozengurt E. J. Biol. Chem. 1997; 272: 9363-9370Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar) and integrin-mediated signaling (30Nojima Y. Morino N. Mimura T. Hamasaki K. Furuya H. Sakai R. Sato T. Tachibana K. Morimoto C. Yazaki Y. Hirai H. J. Biol. Chem. 1995; 270: 15398-15402Crossref PubMed Scopus (292) Google Scholar). As Cas has an SH3-domain as well as multiple SH2-binding motifs, Cas may well assemble a number of proteins such as FAK (20Polte T.R. Hanks S.K. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 10678-10682Crossref PubMed Scopus (386) Google Scholar) and the phosphatases PTP-PEST (31Garton A.J. Flint A.J. Tonks N.K. Mol. Cell. Biol. 1996; 16: 6408-6418Crossref PubMed Scopus (231) Google Scholar) and PTP1B (32Liu F. Hill D.E. Chernoff J. J. Biol. Chem. 1996; 271: 31290-31295Abstract Full Text Full Text PDF PubMed Scopus (204) Google Scholar) into a single complex. Cas may be a critical component by which extracellular events influence cell morphology and survival (33Daniel J.M. Reynolds A.B. Mol. Cell. Biol. 1995; 15: 4819-4824Crossref PubMed Google Scholar, 34Mo Y.Y. Reynolds A.B. Cancer Res. 1996; 56: 2633-2640PubMed Google Scholar, 35Nakamoto T. Sakai R. Honda H. Ogawa S. Ueno H. Suzuki T. Aizawa S. Yazaki Y. Hirai H. Mol. Cell. Biol. 1997; 17: 3884-3897Crossref PubMed Scopus (135) Google Scholar). A theme running through the mechanism by which transcription factors such as AP-1 are activated by receptor tyrosine kinases and integrin receptors is the importance of adaptor proteins. These adaptor proteins contain one or multiple domains that mediate protein-protein or protein-lipid interactions (for review, see Ref. 36Pawson T. Scott J.D. Science. 1997; 278: 2075-2080Crossref PubMed Scopus (1887) Google Scholar). In addition to integrating independent extracellular signals, cell type-specific expression of the adaptor molecules may be critical in determining the cell type-specific response to extracellular stimuli. Although most of the more extensively characterized signal transduction molecules are ubiquitously expressed (15Schaeffer H.J. Catling A.D. Eblen S.T. Collier L.S. Krauss A. Weber M.J. Science. 1998; 281: 1668-1671Crossref PubMed Scopus (384) Google Scholar, 37Nakamura T. Sanokawa R. Sasaki Y. Ayusawa D. Oishi M. Mori N. Oncogene. 1996; 13: 1111-1121PubMed Google Scholar, 38Sun X.J. Pons S. Wang L.M. Zhang Y. Yenush L. Burks D. Myers Jr., M.G. Glasheen E. Copeland N.G. Jenkins N.A. Pierce J.H. White M.F. Mol. Endocrinol. 1997; 11: 251-262Crossref PubMed Scopus (123) Google Scholar), a few adaptor molecules with a limited pattern of expression have been identified, such as N-Shc (37Nakamura T. Sanokawa R. Sasaki Y. Ayusawa D. Oishi M. Mori N. Oncogene. 1996; 13: 1111-1121PubMed Google Scholar) and Grb-IR (39Liu F. Roth R.A. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 10287-10291Crossref PubMed Scopus (150) Google Scholar). To identify additional adaptor proteins that are involved in growth factor and integrin signaling, we have searched an expressed sequence tag (EST) data base for sequences that share homology with SH2-containing adaptor proteins. By this method, we isolated a cDNA encoding a family of novel SH2-containing proteins. The structure and characteristics of at least NSP1 (novelSH2-containing protein 1) suggest that this protein may play an important role in cell proliferation and fetal development. DISCUSSIONWe have isolated a family of novel adaptor proteins (NSP1, NSP2, and NSP3) that contain an N-terminal SH2 domain, a central proline/serine-rich region, and a C-terminal sequence that is distinctive for the NSP proteins. While this manuscript was in preparation, the sequence of NSP2 was published as BCAR3; this protein (BCAR3) appears to be implicated in the development of resistance to the cytostatic agent Taxol (40van Agthoven T. van Agthoven T.L. Dekker A. van der Spek P.J. Vreede L. Dorssers L.C. EMBO J. 1998; 17: 2799-2808Crossref PubMed Scopus (96) Google Scholar). NSP1expression may be restricted to tissues with secretory epithelial cells, whereas NSP2 and NSP3 are expressed in variety of tissues. In hematopoietic tissues, twoNSP3-related transcripts are detected. The coding potential of these two NSP3 transcripts is being explored.NSP1 is phosphorylated in response to insulin and EGF (and insulin-like growth factor I and heregulin (data not shown)), indicating that NSP1 is a common target for a variety of growth factor receptors. In response to EGF, NSP1 associates with the EGF receptor and is phosphorylated. The data are consistent with a direct interaction between the phosphotyrosines on the EGF receptor and the NSP1 SH2 domain and a subsequent receptor kinase-dependent phosphorylation of NSP1. Preliminary data indicate that the SH2 domain alone is able to interact with the EGF receptor, although other regions of NSP1 may also participate in this interaction (data not shown). It is also possible that the EGF receptor-NSP1 interaction is indirect. NSP1 is only modestly phosphorylated in response to integrin signaling. This weak integrin-mediated phosphorylation could conceivably be through FAK or Src-related kinases, both of which are known to associate with Cas (20Polte T.R. Hanks S.K. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 10678-10682Crossref PubMed Scopus (386) Google Scholar, 22Harte M.T. Hildebrand J.D. Burnham M.R. Bouton A.H. Parsons J.T. J. Biol. Chem. 1996; 271: 13649-13655Abstract Full Text Full Text PDF PubMed Scopus (322) Google Scholar, 25Hamasaki K. Mimura T. Morino N. Furuya H. Nakamoto T. Aizawa S. Morimoto C. Yazaki Y. Hirai H. Nojima Y. Biochem. Biophys. Res. Commun. 1996; 222: 338-343Crossref PubMed Scopus (116) Google Scholar, 28Sakai R. Iwamatsu A. Hirano N. Ogawa S. Tanaka T. Mano H. Yazaki Y. Hirai H. EMBO J. 1994; 13: 3748-3756Crossref PubMed Scopus (592) Google Scholar, 41Astier A. Manie S.N. Avraham H. Hirai H. Law S.F. Zhang Y. Golemis E.A. Fu Y. Druker B.J. Haghayeghi N. Freedman A.S. Avraham S. J. Biol. Chem. 1997; 272: 19719-19724Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar).Co-immunoprecipitation experiments revealed that NSP1 interacts with p130Cas. Preliminary data from a yeast two-hybrid analysis are consistent with this result and suggest that the interaction is direct (data not shown). In the co-immunoprecipitation experiments, the interaction between NSP1 and Cas could be detected under conditions in which there was no detectable phosphorylation of NSP1 or Cas, suggesting that the interaction between NSP1 and Cas is phosphorylation-independent and may occur via the SH3 domain in Cas and the proline/serine-rich domain in NSP1. Neither of the demonstrated associations (EGF receptor and Cas) appears to utilize the phosphotyrosines in NSP1. This conclusion is reinforced by the experiments using the tyrosine replacement variants in which both EGF receptor and Cas interactions can occur in the absence of any detectable NSP1 phosphorylation.The relative level of the NSP1·Cas complex and the phosphorylation status of Cas are quite different between receptor tyrosine kinase and integrin signaling. Thus, EGF treatment leads to NSP1 phosphorylation, to dephosphorylation of the Cas that is associated with NSP1, and to an increase in the amount of the NSP·Cas complex. In contrast, in response to fibronectin, there is little change in NSP1 phosphorylation, but there is a significant increase in the phosphorylation of the Cas associated with NSP1. Cas dephosphorylation in response to EGF (42Ojaniemi M. Vuori K. J. Biol. Chem. 1997; 272: 25993-25998Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar) and Cas phosphorylation in response to fibronectin (30Nojima Y. Morino N. Mimura T. Hamasaki K. Furuya H. Sakai R. Sato T. Tachibana K. Morimoto C. Yazaki Y. Hirai H. J. Biol. Chem. 1995; 270: 15398-15402Crossref PubMed Scopus (292) Google Scholar, 43Manie S.N. Astier A. Haghayeghi N. Canty T. Druker B.J. Hirai H. Freedman A.S. J. Biol. Chem. 1997; 272: 15636-15641Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar, 44Vuori K. Hirai H. Aizawa S. Ruoslahti E. Mol. Cell. Biol. 1996; 16: 2606-2613Crossref PubMed Google Scholar) have been previously reported. There is also an apparent dissociation of NSP1 from Cas at short time periods and a subsequent reassociation at longer (4 h) times. These results led to the hypothesis that the biological outcome in response to extracellular signals could be quite distinct in the presence or absence of NSP1. For example, FAK associates with the SH3 region in Cas via a PXXP region at the C terminus of FAK (P715SRP; mouse nomenclature (22Harte M.T. Hildebrand J.D. Burnham M.R. Bouton A.H. Parsons J.T. J. Biol. Chem. 1996; 271: 13649-13655Abstract Full Text Full Text PDF PubMed Scopus (322) Google Scholar)). There are six PXXP signatures in NSP1. Thus, it is possible that NSP1 could compete for the SH3 region in Cas and decrease the amount of FAK that is bound to Cas and so alter FAK-dependent events (21Hanks S.K. Polte T.R. Bioessays. 1997; 19: 137-145Crossref PubMed Scopus (440) Google Scholar). In contrast, EGF treatment leads to NSP1 phosphorylation, to dephosphorylation of NSP1-associated Cas, and to an increase in the amount of the NSP1·Cas complex. This complex is then likely to have a decrease in the number of proteins associated with the phosphotyrosines in Cas and so may lead to changes in downstream signaling.Increased expression of NSP1 results in JNK activation and increased expression from an AP-1-dependent promoter. Whether this activation of JNK is related to the EGF-stimulated phosphorylation of NSP1 or the interaction of Cas with NSP1 is currently unknown, although preliminary data from a luciferase assay indicate that NSP1Y95F, which is not phosphorylated but still interacts with both Cas and the EGF receptor, has diminished but not abolished activity in this assay. It has been previously shown that activation of the JNK kinase cascade is dependent on one of several small GTP-binding proteins (Cdc42, Rac, and Ras) (12Coso O.A. Chiariello M. Yu J.C. Teramoto H. Crespo P. Xu N. Miki T. Gutkind J.S. Cell. 1995; 81: 1137-1146Abstract Full Text PDF PubMed Scopus (1559) Google Scholar, 14Minden A. Lin A. Claret F.X. Abo A. Karin M. Cell. 1995; 81: 1147-1157Abstract Full Text PDF PubMed Scopus (1444) Google Scholar) and on phosphatidylinositol 3-kinase (19Logan S.K. Falasca M. Hu P. Schlessinger J. Mol. Cell. Biol. 1997; 17: 5784-5790Crossref PubMed Scopus (123) Google Scholar). How or whether NSP1 can modify any of these components of the signaling pathway is under investigation.The activation of the c-Jun kinases in response to receptor tyrosine kinase and integrin receptor signaling appears to be critical for regulating cell proliferation (45Antonyak M.A. Moscatello D.K. Wong A.J. J. Biol. Chem. 1998; 273: 2817-2822Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar, 46Bost F. McKay R. Dean N. Mercola D. J. Biol. Chem. 1997; 272: 33422-33429Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar, 47Auer K.L. Contessa J. Brenz-Verca S. Pirola L. Rusconi S. Cooper G. Abo A. Wymann M.P. Davis R.J. Birrer M. Dent P. Mol. Biol. Cell. 1998; 9: 561-573Crossref PubMed Scopus (114) Google Scholar). Furthermore, genetic analysis of JNK signaling in Drosophila (5Ip Y.T. Davis R.J. Curr. Opin. Cell Biol. 1998; 10: 205-219Crossref PubMed Scopus (1374) Google Scholar) and the abnormal liver development in mice genetically lacking the JNK kinase activator MKK4 suggest a critical role for JNK in normal development (48Yang D. Tournier C. Wysk M. Lu H.T. Xu J. Davis R.J. Flavell R.A. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 3004-3009Crossref PubMed Scopus (258) Google Scholar). Thus, the identification of a novel adaptor protein that functions in these processes may provide a valuable molecular tool for understanding cell proliferation and fetal development. We have isolated a family of novel adaptor proteins (NSP1, NSP2, and NSP3) that contain an N-terminal SH2 domain, a central proline/serine-rich region, and a C-terminal sequence that is distinctive for the NSP proteins. While this manuscript was in preparation, the sequence of NSP2 was published as BCAR3; this protein (BCAR3) appears to be implicated in the development of resistance to the cytostatic agent Taxol (40van Agthoven T. van Agthoven T.L. Dekker A. van der Spek P.J. Vreede L. Dorssers L.C. EMBO J. 1998; 17: 2799-2808Crossref PubMed Scopus (96) Google Scholar). NSP1expression may be restricted to tissues with secretory epithelial cells, whereas NSP2 and NSP3 are expressed in variety of tissues. In hematopoietic tissues, twoNSP3-related transcripts are detected. The coding potential of these two NSP3 transcripts is being explored. NSP1 is phosphorylated in response to insulin and EGF (and insulin-like growth factor I and heregulin (data not shown)), indicating that NSP1 is a common target for a variety of growth factor receptors. In response to EGF, NSP1 associates with the EGF receptor and is phosphorylated. The data are consistent with a direct interaction between the phosphotyrosines on the EGF receptor and the NSP1 SH2 domain and a subsequent receptor kinase-dependent phosphorylation of NSP1. Preliminary data indicate that the SH2 domain alone is able to interact with the EGF receptor, although other regions of NSP1 may also participate in this interaction (data not shown). It is also possible that the EGF receptor-NSP1 interaction is indirect. NSP1 is only modestly phosphorylated in response to integrin signaling. This weak integrin-mediated phosphorylation could conceivably be through FAK or Src-related kinases, both of which are known to associate with Cas (20Polte T.R. Hanks S.K. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 10678-10682Crossref PubMed Scopus (386) Google Scholar, 22Harte M.T. Hildebrand J.D. Burnham M.R. Bouton A.H. Parsons J.T. J. Biol. Chem. 1996; 271: 13649-13655Abstract Full Text Full Text PDF PubMed Scopus (322) Google Scholar, 25Hamasaki K. Mimura T. Morino N. Furuya H. Nakamoto T. Aizawa S. Morimoto C. Yazaki Y. Hirai H. Nojima Y. Biochem. Biophys. Res. Commun. 1996; 222: 338-343Crossref PubMed Scopus (116) Google Scholar, 28Sakai R. Iwamatsu A. Hirano N. Ogawa S. Tanaka T. Mano H. Yazaki Y. Hirai H. EMBO J. 1994; 13: 3748-3756Crossref PubMed Scopus (592) Google Scholar, 41Astier A. Manie S.N. Avraham H. Hirai H. Law S.F. Zhang Y. Golemis E.A. Fu Y. Druker B.J. Haghayeghi N. Freedman A.S. Avraham S. J. Biol. Chem. 1997; 272: 19719-19724Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar). Co-immunoprecipitation experiments revealed that NSP1 interacts with p130Cas. Preliminary data from a yeast two-hybrid analysis are consistent with this result and suggest that the interaction is direct (data not shown). In the co-immunoprecipitation experiments, the interaction between NSP1 and Cas could be detected under conditions in which there was no detectable phosphorylation of NSP1 or Cas, suggesting that the interaction between NSP1 and Cas is phosphorylation-independent and may occur via the SH3 domain in Cas and the proline/serine-rich domain in NSP1. Neither of the demonstrated associations (EGF receptor and Cas) appears to utilize the phosphotyrosines in NSP1. This conclusion is reinforced by the experiments using the tyrosine replacement variants in which both EGF receptor and Cas interactions can occur in the absence of any detectable NSP1 phosphorylation. The relative level of the NSP1·Cas complex and the phosphorylation status of Cas are quite different between receptor tyrosine kinase and integrin signaling. Thus, EGF treatment leads to NSP1 phosphorylation, to dephosphorylation of the Cas that is associated with NSP1, and to an increase in the amount of the NSP·Cas complex. In contrast, in response to fibronectin, there is little change in NSP1 phosphorylation, but there is a significant increase in the phosphorylation of the Cas associated with NSP1. Cas dephosphorylation in response to EGF (42Ojaniemi M. Vuori K. J. Biol. Chem. 1997; 272: 25993-25998Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar) and Cas phosphorylation in response to fibronectin (30Nojima Y. Morino N. Mimura T. Hamasaki K. Furuya H. Sakai R. Sato T. Tachibana K. Morimoto C. Yazaki Y. Hirai H. J. Biol. Chem. 1995; 270: 15398-15402Crossref PubMed Scopus (292) Google Scholar, 43Manie S.N. Astier A. Haghayeghi N. Canty T. Druker B.J. Hirai H. Freedman A.S. J. Biol. Chem. 1997; 272: 15636-15641Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar, 44Vuori K. Hirai H. Aizawa S. Ruoslahti E. Mol. Cell. Biol. 1996; 16: 2606-2613Crossref PubMed Google Scholar) have been previously reported. There is also an apparent dissociation of NSP1 from Cas at short time periods and a subsequent reassociation at longer (4 h) times. These results led to the hypothesis that the biological outcome in response to extracellular signals could be quite distinct in the presence or absence of NSP1. For example, FAK associates with the SH3 region in Cas via a PXXP region at the C terminus of FAK (P715SRP; mouse nomenclature (22Harte M.T. Hildebrand J.D. Burnham M.R. Bouton A.H. Parsons J.T. J. Biol. Chem. 1996; 271: 13649-13655Abstract Full Text Full Text PDF PubMed Scopus (322) Google Scholar)). There are six PXXP signatures in NSP1. Thus, it is possible that NSP1 could compete for the SH3 region in Cas and decrease the amount of FAK that is bound to Cas and so alter FAK-dependent events (21Hanks S.K. Polte T.R. Bioessays. 1997; 19: 137-145Crossref PubMed Scopus (440) Google Scholar). In contrast, EGF treatment leads to NSP1 phosphorylation, to dephosphorylation of NSP1-associated Cas, and to an increase in the amount of the NSP1·Cas complex. This complex is then likely to have a decrease in the number of proteins associated with the phosphotyrosines in Cas and so may lead to changes in downstream signaling. Increased expression of NSP1 results in JNK activation and increased expression from an AP-1-dependent promoter. Whether this activation of JNK is related to the EGF-stimulated phosphorylation of NSP1 or the interaction of Cas with NSP1 is currently unknown, although preliminary data from a luciferase assay indicate that NSP1Y95F, which is not phosphorylated but still interacts with both Cas and the EGF receptor, has diminished but not abolished activity in this assay. It has been previously shown that activation of the JNK kinase cascade is dependent on one of several small GTP-binding proteins (Cdc42, Rac, and Ras) (12Coso O.A. Chiariello M. Yu J.C. Teramoto H. Crespo P. Xu N. Miki T. Gutkind J.S. Cell. 1995; 81: 1137-1146Abstract Full Text PDF PubMed Scopus (1559) Google Scholar, 14Minden A. Lin A. Claret F.X. Abo A. Karin M. Cell. 1995; 81: 1147-1157Abstract Full Text PDF PubMed Scopus (1444) Google Scholar) and on phosphatidylinositol 3-kinase (19Logan S.K. Falasca M. Hu P. Schlessinger J. Mol. Cell. Biol. 1997; 17: 5784-5790Crossref PubMed Scopus (123) Google Scholar). How or whether NSP1 can modify any of these components of the signaling pathway is under investigation. The activation of the c-Jun kinases in response to receptor tyrosine kinase and integrin receptor signaling appears to be critical for regulating cell proliferation (45Antonyak M.A. Moscatello D.K. Wong A.J. J. Biol. Chem. 1998; 273: 2817-2822Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar, 46Bost F. McKay R. Dean N. Mercola D. J. Biol. Chem. 1997; 272: 33422-33429Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar, 47Auer K.L. Contessa J. Brenz-Verca S. Pirola L. Rusconi S. Cooper G. Abo A. Wymann M.P. Davis R.J. Birrer M. Dent P. Mol. Biol. Cell. 1998; 9: 561-573Crossref PubMed Scopus (114) Google Scholar). Furthermore, genetic analysis of JNK signaling in Drosophila (5Ip Y.T. Davis R.J. Curr. Opin. Cell Biol. 1998; 10: 205-219Crossref PubMed Scopus (1374) Google Scholar) and the abnormal liver development in mice genetically lacking the JNK kinase activator MKK4 suggest a critical role for JNK in normal development (48Yang D. Tournier C. Wysk M. Lu H.T. Xu J. Davis R.J. Flavell R.A. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 3004-3009Crossref PubMed Scopus (258) Google Scholar). Thus, the identification of a novel adaptor protein that functions in these processes may provide a valuable molecular tool for understanding cell proliferation and fetal development. We thank L. Holzman for the JNK-Myc expression construct and Wayne Anstine and Louis Tamayo for the graphics." @default.
W2077490693 created "2016-06-24" @default.
W2077490693 creator A5010721531 @default.
W2077490693 creator A5083578880 @default.
W2077490693 creator A5088245618 @default.
W2077490693 date "1999-04-01" @default.
W2077490693 modified "2023-10-13" @default.
W2077490693 title "NSP1 Defines a Novel Family of Adaptor Proteins Linking Integrin and Tyrosine Kinase Receptors to the c-Jun N-terminal Kinase/Stress-activated Protein Kinase Signaling Pathway" @default.
W2077490693 cites W1566442216 @default.
W2077490693 cites W1837392873 @default.
W2077490693 cites W1849793110 @default.
W2077490693 cites W1900495018 @default.
W2077490693 cites W1964146094 @default.
W2077490693 cites W1967218150 @default.
W2077490693 cites W1968590447 @default.
W2077490693 cites W1972172786 @default.
W2077490693 cites W1978231615 @default.
W2077490693 cites W1982390204 @default.
W2077490693 cites W1985651693 @default.
W2077490693 cites W1986559713 @default.
W2077490693 cites W1998487776 @default.
W2077490693 cites W2001152066 @default.
W2077490693 cites W2005900169 @default.
W2077490693 cites W2011221649 @default.
W2077490693 cites W2016083882 @default.
W2077490693 cites W2024153969 @default.
W2077490693 cites W2034710767 @default.
W2077490693 cites W2036224418 @default.
W2077490693 cites W2036985660 @default.
W2077490693 cites W2042584344 @default.
W2077490693 cites W2055181868 @default.
W2077490693 cites W2063259786 @default.
W2077490693 cites W2068172713 @default.
W2077490693 cites W2069526456 @default.
W2077490693 cites W2072243374 @default.
W2077490693 cites W2078065785 @default.
W2077490693 cites W2088274904 @default.
W2077490693 cites W2088995677 @default.
W2077490693 cites W2091733793 @default.
W2077490693 cites W2095152292 @default.
W2077490693 cites W2105086994 @default.
W2077490693 cites W2107905355 @default.
W2077490693 cites W2114840684 @default.
W2077490693 cites W2115368090 @default.
W2077490693 cites W2117372001 @default.
W2077490693 cites W2131954729 @default.
W2077490693 cites W2136790603 @default.
W2077490693 cites W2140506935 @default.
W2077490693 cites W2153390050 @default.
W2077490693 cites W2154152087 @default.
W2077490693 cites W2155723800 @default.
W2077490693 cites W2160839395 @default.
W2077490693 cites W4292820908 @default.
W2077490693 doi "https://doi.org/10.1074/jbc.274.15.10047" @default.
W2077490693 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/10187783" @default.
W2077490693 hasPublicationYear "1999" @default.
W2077490693 type Work @default.
W2077490693 sameAs 2077490693 @default.
W2077490693 citedByCount "65" @default.
W2077490693 countsByYear W20774906932012 @default.
W2077490693 countsByYear W20774906932013 @default.
W2077490693 countsByYear W20774906932014 @default.
W2077490693 countsByYear W20774906932016 @default.
W2077490693 countsByYear W20774906932020 @default.
W2077490693 crossrefType "journal-article" @default.
W2077490693 hasAuthorship W2077490693A5010721531 @default.
W2077490693 hasAuthorship W2077490693A5083578880 @default.
W2077490693 hasAuthorship W2077490693A5088245618 @default.
W2077490693 hasBestOaLocation W20774906931 @default.
W2077490693 hasConcept C101544691 @default.
W2077490693 hasConcept C124160383 @default.
W2077490693 hasConcept C130523297 @default.
W2077490693 hasConcept C137361374 @default.
W2077490693 hasConcept C159479382 @default.
W2077490693 hasConcept C170493617 @default.
W2077490693 hasConcept C180361614 @default.
W2077490693 hasConcept C183786373 @default.
W2077490693 hasConcept C184235292 @default.
W2077490693 hasConcept C185592680 @default.
W2077490693 hasConcept C2775960820 @default.
W2077490693 hasConcept C55493867 @default.
W2077490693 hasConcept C59143045 @default.
W2077490693 hasConcept C62478195 @default.
W2077490693 hasConcept C82495950 @default.
W2077490693 hasConcept C86803240 @default.
W2077490693 hasConcept C90934575 @default.
W2077490693 hasConcept C95444343 @default.
W2077490693 hasConcept C97029542 @default.
W2077490693 hasConceptScore W2077490693C101544691 @default.
W2077490693 hasConceptScore W2077490693C124160383 @default.
W2077490693 hasConceptScore W2077490693C130523297 @default.
W2077490693 hasConceptScore W2077490693C137361374 @default.
W2077490693 hasConceptScore W2077490693C159479382 @default.
W2077490693 hasConceptScore W2077490693C170493617 @default.
W2077490693 hasConceptScore W2077490693C180361614 @default.
W2077490693 hasConceptScore W2077490693C183786373 @default.
W2077490693 hasConceptScore W2077490693C184235292 @default.
W2077490693 hasConceptScore W2077490693C185592680 @default.