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W2061002918 abstract "An ∼37-kDa cytoplasmic protein is rapidly tyrosine-phosphorylated in the response of mouse BAC1.2F5 macrophages to colony stimulating factor-1 (CSF-1). pp37 was purified from the cytosolic fraction by anti-Tyr(P) affinity chromatography, size exclusion chromatography, and C4 reverse phase high pressure liquid chromatography. The sequences of four peptides derived from the purified protein matched portions of an expressed sequence tag (EST) sequence, and the EST clone was used to obtain cDNA clones encoding the pp37 protein, which shares sequence similarity with the PST PIP (proline, serine,threonine phosphatase interactingprotein)/CDC15 family of protein-tyrosine phosphatase substrates. pp37 is predicted to contain a Fes/CIP4 homology (FCH) domain and an actin-binding domain-like sequence. It is expressed selectively in macrophages, macrophage cell lines, and at low levels in macrophage-containing tissues. pp37 is predominantly found in the cytosol, where it is associated with actin. However, ∼4% resides in the membrane fraction, and the trace amount in the cytoskeletal fraction is increased by CSF-1 stimulation. Termedmacrophage actin-associated tyrosine-phosphorylated protein (MAYP), p37 is the major F-actin-associated protein that is tyrosine-phosphorylated in macrophages and is likely to play a role in regulating the CSF-1-induced reorganization of the actin cytoskeleton. An ∼37-kDa cytoplasmic protein is rapidly tyrosine-phosphorylated in the response of mouse BAC1.2F5 macrophages to colony stimulating factor-1 (CSF-1). pp37 was purified from the cytosolic fraction by anti-Tyr(P) affinity chromatography, size exclusion chromatography, and C4 reverse phase high pressure liquid chromatography. The sequences of four peptides derived from the purified protein matched portions of an expressed sequence tag (EST) sequence, and the EST clone was used to obtain cDNA clones encoding the pp37 protein, which shares sequence similarity with the PST PIP (proline, serine,threonine phosphatase interactingprotein)/CDC15 family of protein-tyrosine phosphatase substrates. pp37 is predicted to contain a Fes/CIP4 homology (FCH) domain and an actin-binding domain-like sequence. It is expressed selectively in macrophages, macrophage cell lines, and at low levels in macrophage-containing tissues. pp37 is predominantly found in the cytosol, where it is associated with actin. However, ∼4% resides in the membrane fraction, and the trace amount in the cytoskeletal fraction is increased by CSF-1 stimulation. Termedmacrophage actin-associated tyrosine-phosphorylated protein (MAYP), p37 is the major F-actin-associated protein that is tyrosine-phosphorylated in macrophages and is likely to play a role in regulating the CSF-1-induced reorganization of the actin cytoskeleton. colony stimulating factor-1 CSF-1 receptor endoproteinase-Arg-C expressed sequence tag Fes/CIP4 homology iodoacetic acid macrophage actin-associated tyrosine-phosphorylated protein proline, serine, threonine phosphatase interacting protein phosphotyrosine protein-tyrosine phosphatase PTP-hematopoietic stem cell fraction reverse phase high pressure liquid chromatography polyacrylamide gel electrophoresis Wiskott-Aldrich syndrome protein bone marrow-derived macrophages polymerase chain reaction kilobase pair(s) horseradish peroxidase open reading frame amino acids. The survival, proliferation, and differentiation of mononuclear phagocytic cells is regulated by the growth factor, colony stimulating factor-1 (CSF-1),1 via its specific interaction with the CSF-1 receptor (CSF-1R), a protein-tyrosine kinase encoded by the c-fms proto-oncogene product (reviewed in Refs. 1Stanley E.R. Thomson A.W. The Cytokine Handbook. Academic Press, San Diego, CA1994: 387-418Google Scholar, 2Pollard J.W. Stanley E.R. Adv. Dev. Biochem. 1996; 4: 153-193Crossref Google Scholar, 3Sherr C.J. Rettenmier C.W. Sacca R. Roussel M.F. Look A.T. Stanley E.R. Cell. 1985; 41: 665-676Abstract Full Text PDF PubMed Scopus (977) Google Scholar). Incubation of macrophages with CSF-1 causes CSF-1R dimerization, activation, and tyrosine phosphorylation, followed at 1 min after CSF-1 addition by the tyrosine phosphorylation of several, primarily cytoplasmic, proteins, usually associated in complexes with cytoskeletal and/or signaling proteins (4Li W. Stanley E.R. EMBO J. 1991; 10: 277-288Crossref PubMed Scopus (113) Google Scholar, 5Li W. Yeung Y.-G. Stanley E.R. J. Biol. Chem. 1991; 266: 6808-6814Abstract Full Text PDF PubMed Google Scholar, 6Baccarini M. Li W. Dello Sbarba P. Stanley E.R. Receptor. 1991; 1: 243-259PubMed Google Scholar, 7Sengupta A. Liu W.-K. Yeung Y.-G. Yeung D.C.-Y. Frackelton A.R. Stanley E.R. Proc. Natl. Acad. Sci. U. S. A. 1988; 85: 8062-8066Crossref PubMed Scopus (69) Google Scholar, 8Downing J.R. Rettenmier C.W. Sherr C.J. Mol. Cell. Biol. 1988; 8: 1795-1799Crossref PubMed Scopus (57) Google Scholar, 9Yeung Y.-G. Wang Y. Einstein D.B. Stanley E.R. J. Biol. Chem. 1998; 273: 17128-17137Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar). The tyrosine phosphorylation of the non-CSF-1R proteins may be directly or indirectly mediated by the CSF-1R-kinase or may increase due to growth factor-induced inhibition of a protein-tyrosine phosphatase (PTP).We have used direct purification and sequencing approaches, to identify several tyrosine-phosphorylated proteins, including the PTP, SHP-1, and Shc, as well as several cytoskeletal and/or signaling molecules associated with them (9Yeung Y.-G. Wang Y. Einstein D.B. Stanley E.R. J. Biol. Chem. 1998; 273: 17128-17137Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar, 10Yeung Y.-G. Berg K.L. Pixley F.J. Angeletti R.H. Stanley E.R. J. Biol. Chem. 1992; 267: 23447-23450Abstract Full Text PDF PubMed Google Scholar). In this paper, we describe the characterization of the major macrophage F-actin-associated tyrosine-phosphorylatedprotein (MAYP). This 37-kDa protein shares sequence similarity with a family of PTP substrates, is selectively expressed in macrophages and following CSF-1 stimulation, exhibits increased tyrosine phosphorylation, and is increased in the cytoskeletal fraction.DISCUSSIONPrevious phalloidin co-precipitation experiments indicated that pp37 was the most prominent F-actin-associated tyrosine-phosphorylated protein in the cytosolic fraction of CSF-1-stimulated macrophages (9Yeung Y.-G. Wang Y. Einstein D.B. Stanley E.R. J. Biol. Chem. 1998; 273: 17128-17137Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar). The present study establishes the identity of pp37 as MAYP and indicates that it is related to a group of PTP substrates, one of which has been shown to play an important role in regulation of the actin cytoskeleton. From its pattern of expression in cell lines, MAYP appears to be selectively expressed in macrophages (i.e.BAC1.2F5, BMM, and J774.2 cells), rather than less mature mononuclear phagocyte progenitor cells (i.e. M1 and WEHI-3 cells) and not at all in some other cell types, including fibroblasts, erythroid progenitors, and mast cells. MAYP exhibits a low level of tyrosine phosphorylation in unstimulated macrophages that is increased 4–6-fold by stimulation with CSF-1. Although the vast majority of MAYP resides in the cytosolic fraction, ∼4% resides in the membrane fraction and a trace amount in the cytoskeletal fraction. Upon stimulation with CSF-1, the proportion of MAYP in the cytoskeletal fraction is rapidly increased. Treatment with IAA alone increases the proportion of tyrosine-phosphorylated MAYP by 27-fold and increases the proportion of membrane associated MAYP by 6-fold. It is therefore possible that stimulation with CSF-1 alone, which increases tyrosine phosphorylation by only ∼5-fold, is associated with a movement of MAYP to the membrane that is below the level of detection and that membrane association may require tyrosine phosphorylation of MAYP. Interestingly, cytosolic MAYP is constitutively associated with actin (Fig. 5; Ref. 9Yeung Y.-G. Wang Y. Einstein D.B. Stanley E.R. J. Biol. Chem. 1998; 273: 17128-17137Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar). These data suggest that MAYP may be involved in regulating some of the rapid, CSF-1-induced cytoskeletal changes that take place within minutes of macrophage stimulation with CSF-1 (11Morgan C.J. Pollard J.W. Stanley E.R. J. Cell. Physiol. 1987; 130: 420-427Crossref PubMed Scopus (150) Google Scholar, 18Boocock C.A. Jones G.E. Stanley E.R. Pollard J.W. J. Cell Sci. 1989; 93: 447-456PubMed Google Scholar,19Webb S.E. Pollard J.W. Jones G.E. J. Cell Sci. 1996; 109: 793-803PubMed Google Scholar).MAYP, PST PIP, and CDC15 share FCH domains, coiled-coil domains, and basic and acidic amino acid-rich regions. PST PIP was identified by a yeast two-hybrid screen with the PEST-type PTP, PTP hematopoietic stem cell fraction (PTP-HSCF) (20Spencer S. Dowbenko D. Cheng J. Li W.L. Brush J. Utzig S. Simanis V. Lasky L.A. J. Cell Biol. 1997; 138: 845-860Crossref PubMed Scopus (151) Google Scholar), which is expressed in hematopoietic stem/progenitor cells and fetal thymus, but not in more differentiated cells, including macrophages (21Cheng J. Daimaru L. Fennie C. Lasky L. Blood. 1996; 88: 1156-1167Crossref PubMed Google Scholar, 22Dosil M. Leibman N. Lemischka I.R. Blood. 1996; 88: 4510-4525Crossref PubMed Google Scholar). PST PIP appears to be the ortholog of the actin-associated Schizosaccharomyces pombeprotein, CDC15p, a phosphorylated protein implicated in the assembly of the actin ring in the cytokinetic furrow (20Spencer S. Dowbenko D. Cheng J. Li W.L. Brush J. Utzig S. Simanis V. Lasky L.A. J. Cell Biol. 1997; 138: 845-860Crossref PubMed Scopus (151) Google Scholar, 23Fankhauser C. Reymond A. Cerutti L. Utzig S. Hofmann K. Simanis V. Cell. 1995; 82: 435-444Abstract Full Text PDF PubMed Scopus (222) Google Scholar). Association of PST PIP with PTP-HSCF involves the proline-rich region of the phosphatase and the coiled-coil domains of PST PIP. In co-transfection experiments in COS cells, PST PIP was shown to be tyrosine-phosphorylated by v-Src and dephosphorylated by its associated PTP-HSCF. PST PIP is co-localized with F-actin-rich regions (cortical actin cytoskeleton, actin stress fibers, lamellopodia) in interphase cells and with cortical actin and the cytokinetic furrow in cells undergoing cytokinesis (20Spencer S. Dowbenko D. Cheng J. Li W.L. Brush J. Utzig S. Simanis V. Lasky L.A. J. Cell Biol. 1997; 138: 845-860Crossref PubMed Scopus (151) Google Scholar). More recently, its role in the regulation of the actin cytoskeleton was further emphasized by the demonstration that the interaction between the PST PIP SH3 domain and proline-rich regions of Wiskott-Aldrich syndrome protein (WASP) results in a loss of actin bundling activity by the COOH terminus of WASP and that tyrosine phosphorylation in the polyproline binding pocket of the SH3 domain of PST PIP inhibits binding of PST PIP and WASP, releasing WASP and PST PIP for their independent functioning elsewhere in the cell (24Wu Y. Spencer S.D. Lasky L.A. J. Biol. Chem. 1998; 273: 5765-5770Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar).Three features of MAYP suggest that its function and regulation in cells differ from the function and regulation of PST PIP. First, MAYP appears to be selectively expressed in macrophages and within the mononuclear phagocytic lineage has the inverse expression pattern of PTP-HSCF, which is expressed in more primitive cells and not in macrophages (21Cheng J. Daimaru L. Fennie C. Lasky L. Blood. 1996; 88: 1156-1167Crossref PubMed Google Scholar, 22Dosil M. Leibman N. Lemischka I.R. Blood. 1996; 88: 4510-4525Crossref PubMed Google Scholar). For this reason, MAYP is unlikely to be regulated by PTP-HSCF. Second, MAYP differs from PST PIP/CDC15 in that it lacks the SH3 domain of PST PIP that appears to be critical for its modulatory effect on WASP. Third, the existence of a human EST sharing 95% sequence similarity with MAYP indicates that MAYP is not the mouse homolog of human PST PIP.Despite these differences, MAYP shares several features in common with PST PIP that suggest that they could function in a similar manner. First, they share a region of sequence similarity that includes an FCH domain, a coiled-coil domain, and a region rich in basic and acidic amino acids. Second, the increased tyrosine phosphorylation of MAYP in the presence of IAA could be due to inhibition of a closely associated PTP, akin to the regulation of PST PIP by PTP-HSCF. Third, MAYP binds F-actin, and PST PIP is clearly intimately involved in regulating the actin cytoskeleton.The possibility that MAYP is involved in regulation of the actin cytoskeleton is appealing because of the presence of both the FCH domain and regions sharing sequence similarity with known actin-binding domains and because of the rapid reorganization of actin observed in response to CSF-1 (18Boocock C.A. Jones G.E. Stanley E.R. Pollard J.W. J. Cell Sci. 1989; 93: 447-456PubMed Google Scholar, 19Webb S.E. Pollard J.W. Jones G.E. J. Cell Sci. 1996; 109: 793-803PubMed Google Scholar). The FCH domain has been found to occur at the extreme NH2 terminus of the nonreceptor tyrosine kinase FER, the Fujinami Sarcoma virus Fes/Fps family of proto-oncogene products, the RhoGAP protein p115, mouse proteins h74, and the growth arrest-specific gene product as well as two gene products fromCaenorhabditis elegans (FO9E10.9 and F45E1.7) and one fromS. cerevisiae. Several of these proteins have potential roles in organizing Rho proteins and the actin cytoskeleton. It has been suggested that the FCH domains may bind functionally related target molecules (25Aspenström P. Curr. Biol. 1997; 7: 479-487Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar). The coiled coil domain of MAYP is highly conserved with the central coiled coil domain of PST PIP (67% identity). These domains are also rich in lysine and arginine residues and resemble sequences present in several actin-binding proteins (16Vandekerckhove J. Curr. Opin. Cell Biol. 1990; 2: 41-50Crossref PubMed Scopus (124) Google Scholar,17Friederick E. Vancompernolle K. Huet C. Goethals M. Finidori J. Vandekerckhove J. Louvard D. Cell. 1992; 70: 81-92Abstract Full Text PDF PubMed Scopus (141) Google Scholar), including paramyosin, myosin heavy chain, and troponin. While PST PIP has not been reported to bind actin, its function is intimately involved in the regulation of F-actin. Thus the association of MAYP with F-actin and its close relationship to PST PIP are intriguing, particularly in view of the rapid reorganization of the cytoskeleton observed in response to CSF-1, that follows MAYP tyrosine phosphorylation. Obviously, it will be important to identify the PTP(s) and kinase(s) that regulate MAYP tyrosine phosphorylation, the mechanism by which MAYP associates with actin and its functional role in the CSF-1 response of macrophages. The survival, proliferation, and differentiation of mononuclear phagocytic cells is regulated by the growth factor, colony stimulating factor-1 (CSF-1),1 via its specific interaction with the CSF-1 receptor (CSF-1R), a protein-tyrosine kinase encoded by the c-fms proto-oncogene product (reviewed in Refs. 1Stanley E.R. Thomson A.W. The Cytokine Handbook. Academic Press, San Diego, CA1994: 387-418Google Scholar, 2Pollard J.W. Stanley E.R. Adv. Dev. Biochem. 1996; 4: 153-193Crossref Google Scholar, 3Sherr C.J. Rettenmier C.W. Sacca R. Roussel M.F. Look A.T. Stanley E.R. Cell. 1985; 41: 665-676Abstract Full Text PDF PubMed Scopus (977) Google Scholar). Incubation of macrophages with CSF-1 causes CSF-1R dimerization, activation, and tyrosine phosphorylation, followed at 1 min after CSF-1 addition by the tyrosine phosphorylation of several, primarily cytoplasmic, proteins, usually associated in complexes with cytoskeletal and/or signaling proteins (4Li W. Stanley E.R. EMBO J. 1991; 10: 277-288Crossref PubMed Scopus (113) Google Scholar, 5Li W. Yeung Y.-G. Stanley E.R. J. Biol. Chem. 1991; 266: 6808-6814Abstract Full Text PDF PubMed Google Scholar, 6Baccarini M. Li W. Dello Sbarba P. Stanley E.R. Receptor. 1991; 1: 243-259PubMed Google Scholar, 7Sengupta A. Liu W.-K. Yeung Y.-G. Yeung D.C.-Y. Frackelton A.R. Stanley E.R. Proc. Natl. Acad. Sci. U. S. A. 1988; 85: 8062-8066Crossref PubMed Scopus (69) Google Scholar, 8Downing J.R. Rettenmier C.W. Sherr C.J. Mol. Cell. Biol. 1988; 8: 1795-1799Crossref PubMed Scopus (57) Google Scholar, 9Yeung Y.-G. Wang Y. Einstein D.B. Stanley E.R. J. Biol. Chem. 1998; 273: 17128-17137Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar). The tyrosine phosphorylation of the non-CSF-1R proteins may be directly or indirectly mediated by the CSF-1R-kinase or may increase due to growth factor-induced inhibition of a protein-tyrosine phosphatase (PTP). We have used direct purification and sequencing approaches, to identify several tyrosine-phosphorylated proteins, including the PTP, SHP-1, and Shc, as well as several cytoskeletal and/or signaling molecules associated with them (9Yeung Y.-G. Wang Y. Einstein D.B. Stanley E.R. J. Biol. Chem. 1998; 273: 17128-17137Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar, 10Yeung Y.-G. Berg K.L. Pixley F.J. Angeletti R.H. Stanley E.R. J. Biol. Chem. 1992; 267: 23447-23450Abstract Full Text PDF PubMed Google Scholar). In this paper, we describe the characterization of the major macrophage F-actin-associated tyrosine-phosphorylatedprotein (MAYP). This 37-kDa protein shares sequence similarity with a family of PTP substrates, is selectively expressed in macrophages and following CSF-1 stimulation, exhibits increased tyrosine phosphorylation, and is increased in the cytoskeletal fraction. DISCUSSIONPrevious phalloidin co-precipitation experiments indicated that pp37 was the most prominent F-actin-associated tyrosine-phosphorylated protein in the cytosolic fraction of CSF-1-stimulated macrophages (9Yeung Y.-G. Wang Y. Einstein D.B. Stanley E.R. J. Biol. Chem. 1998; 273: 17128-17137Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar). The present study establishes the identity of pp37 as MAYP and indicates that it is related to a group of PTP substrates, one of which has been shown to play an important role in regulation of the actin cytoskeleton. From its pattern of expression in cell lines, MAYP appears to be selectively expressed in macrophages (i.e.BAC1.2F5, BMM, and J774.2 cells), rather than less mature mononuclear phagocyte progenitor cells (i.e. M1 and WEHI-3 cells) and not at all in some other cell types, including fibroblasts, erythroid progenitors, and mast cells. MAYP exhibits a low level of tyrosine phosphorylation in unstimulated macrophages that is increased 4–6-fold by stimulation with CSF-1. Although the vast majority of MAYP resides in the cytosolic fraction, ∼4% resides in the membrane fraction and a trace amount in the cytoskeletal fraction. Upon stimulation with CSF-1, the proportion of MAYP in the cytoskeletal fraction is rapidly increased. Treatment with IAA alone increases the proportion of tyrosine-phosphorylated MAYP by 27-fold and increases the proportion of membrane associated MAYP by 6-fold. It is therefore possible that stimulation with CSF-1 alone, which increases tyrosine phosphorylation by only ∼5-fold, is associated with a movement of MAYP to the membrane that is below the level of detection and that membrane association may require tyrosine phosphorylation of MAYP. Interestingly, cytosolic MAYP is constitutively associated with actin (Fig. 5; Ref. 9Yeung Y.-G. Wang Y. Einstein D.B. Stanley E.R. J. Biol. Chem. 1998; 273: 17128-17137Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar). These data suggest that MAYP may be involved in regulating some of the rapid, CSF-1-induced cytoskeletal changes that take place within minutes of macrophage stimulation with CSF-1 (11Morgan C.J. Pollard J.W. Stanley E.R. J. Cell. Physiol. 1987; 130: 420-427Crossref PubMed Scopus (150) Google Scholar, 18Boocock C.A. Jones G.E. Stanley E.R. Pollard J.W. J. Cell Sci. 1989; 93: 447-456PubMed Google Scholar,19Webb S.E. Pollard J.W. Jones G.E. J. Cell Sci. 1996; 109: 793-803PubMed Google Scholar).MAYP, PST PIP, and CDC15 share FCH domains, coiled-coil domains, and basic and acidic amino acid-rich regions. PST PIP was identified by a yeast two-hybrid screen with the PEST-type PTP, PTP hematopoietic stem cell fraction (PTP-HSCF) (20Spencer S. Dowbenko D. Cheng J. Li W.L. Brush J. Utzig S. Simanis V. Lasky L.A. J. Cell Biol. 1997; 138: 845-860Crossref PubMed Scopus (151) Google Scholar), which is expressed in hematopoietic stem/progenitor cells and fetal thymus, but not in more differentiated cells, including macrophages (21Cheng J. Daimaru L. Fennie C. Lasky L. Blood. 1996; 88: 1156-1167Crossref PubMed Google Scholar, 22Dosil M. Leibman N. Lemischka I.R. Blood. 1996; 88: 4510-4525Crossref PubMed Google Scholar). PST PIP appears to be the ortholog of the actin-associated Schizosaccharomyces pombeprotein, CDC15p, a phosphorylated protein implicated in the assembly of the actin ring in the cytokinetic furrow (20Spencer S. Dowbenko D. Cheng J. Li W.L. Brush J. Utzig S. Simanis V. Lasky L.A. J. Cell Biol. 1997; 138: 845-860Crossref PubMed Scopus (151) Google Scholar, 23Fankhauser C. Reymond A. Cerutti L. Utzig S. Hofmann K. Simanis V. Cell. 1995; 82: 435-444Abstract Full Text PDF PubMed Scopus (222) Google Scholar). Association of PST PIP with PTP-HSCF involves the proline-rich region of the phosphatase and the coiled-coil domains of PST PIP. In co-transfection experiments in COS cells, PST PIP was shown to be tyrosine-phosphorylated by v-Src and dephosphorylated by its associated PTP-HSCF. PST PIP is co-localized with F-actin-rich regions (cortical actin cytoskeleton, actin stress fibers, lamellopodia) in interphase cells and with cortical actin and the cytokinetic furrow in cells undergoing cytokinesis (20Spencer S. Dowbenko D. Cheng J. Li W.L. Brush J. Utzig S. Simanis V. Lasky L.A. J. Cell Biol. 1997; 138: 845-860Crossref PubMed Scopus (151) Google Scholar). More recently, its role in the regulation of the actin cytoskeleton was further emphasized by the demonstration that the interaction between the PST PIP SH3 domain and proline-rich regions of Wiskott-Aldrich syndrome protein (WASP) results in a loss of actin bundling activity by the COOH terminus of WASP and that tyrosine phosphorylation in the polyproline binding pocket of the SH3 domain of PST PIP inhibits binding of PST PIP and WASP, releasing WASP and PST PIP for their independent functioning elsewhere in the cell (24Wu Y. Spencer S.D. Lasky L.A. J. Biol. Chem. 1998; 273: 5765-5770Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar).Three features of MAYP suggest that its function and regulation in cells differ from the function and regulation of PST PIP. First, MAYP appears to be selectively expressed in macrophages and within the mononuclear phagocytic lineage has the inverse expression pattern of PTP-HSCF, which is expressed in more primitive cells and not in macrophages (21Cheng J. Daimaru L. Fennie C. Lasky L. Blood. 1996; 88: 1156-1167Crossref PubMed Google Scholar, 22Dosil M. Leibman N. Lemischka I.R. Blood. 1996; 88: 4510-4525Crossref PubMed Google Scholar). For this reason, MAYP is unlikely to be regulated by PTP-HSCF. Second, MAYP differs from PST PIP/CDC15 in that it lacks the SH3 domain of PST PIP that appears to be critical for its modulatory effect on WASP. Third, the existence of a human EST sharing 95% sequence similarity with MAYP indicates that MAYP is not the mouse homolog of human PST PIP.Despite these differences, MAYP shares several features in common with PST PIP that suggest that they could function in a similar manner. First, they share a region of sequence similarity that includes an FCH domain, a coiled-coil domain, and a region rich in basic and acidic amino acids. Second, the increased tyrosine phosphorylation of MAYP in the presence of IAA could be due to inhibition of a closely associated PTP, akin to the regulation of PST PIP by PTP-HSCF. Third, MAYP binds F-actin, and PST PIP is clearly intimately involved in regulating the actin cytoskeleton.The possibility that MAYP is involved in regulation of the actin cytoskeleton is appealing because of the presence of both the FCH domain and regions sharing sequence similarity with known actin-binding domains and because of the rapid reorganization of actin observed in response to CSF-1 (18Boocock C.A. Jones G.E. Stanley E.R. Pollard J.W. J. Cell Sci. 1989; 93: 447-456PubMed Google Scholar, 19Webb S.E. Pollard J.W. Jones G.E. J. Cell Sci. 1996; 109: 793-803PubMed Google Scholar). The FCH domain has been found to occur at the extreme NH2 terminus of the nonreceptor tyrosine kinase FER, the Fujinami Sarcoma virus Fes/Fps family of proto-oncogene products, the RhoGAP protein p115, mouse proteins h74, and the growth arrest-specific gene product as well as two gene products fromCaenorhabditis elegans (FO9E10.9 and F45E1.7) and one fromS. cerevisiae. Several of these proteins have potential roles in organizing Rho proteins and the actin cytoskeleton. It has been suggested that the FCH domains may bind functionally related target molecules (25Aspenström P. Curr. Biol. 1997; 7: 479-487Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar). The coiled coil domain of MAYP is highly conserved with the central coiled coil domain of PST PIP (67% identity). These domains are also rich in lysine and arginine residues and resemble sequences present in several actin-binding proteins (16Vandekerckhove J. Curr. Opin. Cell Biol. 1990; 2: 41-50Crossref PubMed Scopus (124) Google Scholar,17Friederick E. Vancompernolle K. Huet C. Goethals M. Finidori J. Vandekerckhove J. Louvard D. Cell. 1992; 70: 81-92Abstract Full Text PDF PubMed Scopus (141) Google Scholar), including paramyosin, myosin heavy chain, and troponin. While PST PIP has not been reported to bind actin, its function is intimately involved in the regulation of F-actin. Thus the association of MAYP with F-actin and its close relationship to PST PIP are intriguing, particularly in view of the rapid reorganization of the cytoskeleton observed in response to CSF-1, that follows MAYP tyrosine phosphorylation. Obviously, it will be important to identify the PTP(s) and kinase(s) that regulate MAYP tyrosine phosphorylation, the mechanism by which MAYP associates with actin and its functional role in the CSF-1 response of macrophages. Previous phalloidin co-precipitation experiments indicated that pp37 was the most prominent F-actin-associated tyrosine-phosphorylated protein in the cytosolic fraction of CSF-1-stimulated macrophages (9Yeung Y.-G. Wang Y. Einstein D.B. Stanley E.R. J. Biol. Chem. 1998; 273: 17128-17137Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar). The present study establishes the identity of pp37 as MAYP and indicates that it is related to a group of PTP substrates, one of which has been shown to play an important role in regulation of the actin cytoskeleton. From its pattern of expression in cell lines, MAYP appears to be selectively expressed in macrophages (i.e.BAC1.2F5, BMM, and J774.2 cells), rather than less mature mononuclear phagocyte progenitor cells (i.e. M1 and WEHI-3 cells) and not at all in some other cell types, including fibroblasts, erythroid progenitors, and mast cells. MAYP exhibits a low level of tyrosine phosphorylation in unstimulated macrophages that is increased 4–6-fold by stimulation with CSF-1. Although the vast majority of MAYP resides in the cytosolic fraction, ∼4% resides in the membrane fraction and a trace amount in the cytoskeletal fraction. Upon stimulation with CSF-1, the proportion of MAYP in the cytoskeletal fraction is rapidly increased. Treatment with IAA alone increases the proportion of tyrosine-phosphorylated MAYP by 27-fold and increases the proportion of membrane associated MAYP by 6-fold. It is therefore possible that stimulation with CSF-1 alone, which increases tyrosine phosphorylation by only ∼5-fold, is associated with a movement of MAYP to the membrane that is below the level of detection and that membrane association may require tyrosine phosphorylation of MAYP. Interestingly, cytosolic MAYP is constitutively associated with actin (Fig. 5; Ref. 9Yeung Y.-G. Wang Y. Einstein D.B. Stanley E.R. J. Biol. Chem. 1998; 273: 17128-17137Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar). These data suggest that MAYP may be involved in regulating some of the rapid, CSF-1-induced cytoskeletal changes that take place within minutes of macrophage stimulation with CSF-1 (11Morgan C.J. Pollard J.W. Stanley E.R. J. Cell. Physiol. 1987; 130: 420-427Crossref PubMed Scopus (150) Google Scholar, 18Boocock C.A. Jones G.E. Stanley E.R. Pollard J.W. J. Cell Sci. 1989; 93: 447-456PubMed Google Scholar,19Webb S.E. Pollard J.W. Jones G.E. J. Cell Sci. 1996; 109: 793-803PubMed Google Scholar). MAYP, PST PIP, and CDC15 share FCH domains, coiled-coil domains, and basic and acidic amino acid-rich regions. PST PIP was identified by a yeast two-hybrid screen with the PEST-type PTP, PTP hematopoietic stem cell fraction (PTP-HSCF) (20Spencer S. Dowbenko D. Cheng J. Li W.L. Brush J. Utzig S. Simanis V. Lasky L.A. J. Cell Biol. 1997; 138: 845-860Crossref PubMed Scopus (151) Google Scholar), which is expressed in hematopoietic stem/progenitor cells and fetal thymus, but not in more differentiated cells, including macrophages (21Cheng J. Daimaru L. Fennie C. Lasky L. Blood. 1996; 88: 1156-1167Crossref PubMed Google Scholar, 22Dosil M. Leibman N. Lemischka I.R. Blood. 1996; 88: 4510-4525Crossref PubMed Google Scholar). PST PIP appears to be the ortholog of the actin-associated Schizosaccharomyces pombeprotein, CDC15p, a phosphorylated protein implicated in the assembly of the actin ring in the cytokinetic furrow (20Spencer S. Dowbenko D. Cheng J. Li W.L. Brush J. Utzig S. Simanis V. Lasky L.A. J. Cell Biol. 1997; 138: 845-860Crossref PubMed Scopus (151) Google Scholar, 23Fankhauser C. Reymond A. Cerutti L. Utzig S. Hofmann K. Simanis V. Cell. 1995; 82: 435-444Abstract Full Text PDF PubMed Scopus (222) Google Scholar). Association of PST PIP with PTP-HSCF involves the proline-rich region of the phosphatase and the coiled-coil domains of PST PIP. In co-transfection experiments in COS cells, PST PIP was shown to be tyrosine-phosphorylated by v-Src and dephosphorylated by its associated PTP-HSCF. PST PIP is co-localized with F-actin-rich regions (cortical actin cytoskeleton, actin stress fibers, lamellopodia) in interphase cells and with cortical actin and the cytokinetic furrow in cells undergoing cytokinesis (20Spencer S. Dowbenko D. Cheng J. Li W.L. Brush J. Utzig S. Simanis V. Lasky L.A. J. Cell Biol. 1997; 138: 845-860Crossref PubMed Scopus (151) Google Scholar). More recently, its role in the regulation of the actin cytoskeleton was further emphasized by the demonstration that the interaction between the PST PIP SH3 domain and proline-rich regions of Wiskott-Aldrich syndrome protein (WASP) results in a loss of actin bundling activity by the COOH terminus of WASP and that tyrosine phosphorylation in the polyproline binding pocket of the SH3 domain of PST PIP inhibits binding of PST PIP and WASP, releasing WASP and PST PIP for their independent functioning elsewhere in the cell (24Wu Y. Spencer S.D. Lasky L.A. J. Biol. Chem. 1998; 273: 5765-5770Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar). Three features of MAYP suggest that its function and regulation in cells differ from the function and regulation of PST PIP. First, MAYP appears to be selectively expressed in macrophages and within the mononuclear phagocytic lineage has the inverse expression pattern of PTP-HSCF, which is expressed in more primitive cells and not in macrophages (21Cheng J. Daimaru L. Fennie C. Lasky L. Blood. 1996; 88: 1156-1167Crossref PubMed Google Scholar, 22Dosil M. Leibman N. Lemischka I.R. Blood. 1996; 88: 4510-4525Crossref PubMed Google Scholar). For this reason, MAYP is unlikely to be regulated by PTP-HSCF. Second, MAYP differs from PST PIP/CDC15 in that it lacks the SH3 domain of PST PIP that appears to be critical for its modulatory effect on WASP. Third, the existence of a human EST sharing 95% sequence similarity with MAYP indicates that MAYP is not the mouse homolog of human PST PIP. Despite these differences, MAYP shares several features in common with PST PIP that suggest that they could function in a similar manner. First, they share a region of sequence similarity that includes an FCH domain, a coiled-coil domain, and a region rich in basic and acidic amino acids. Second, the increased tyrosine phosphorylation of MAYP in the presence of IAA could be due to inhibition of a closely associated PTP, akin to the regulation of PST PIP by PTP-HSCF. Third, MAYP binds F-actin, and PST PIP is clearly intimately involved in regulating the actin cytoskeleton. The possibility that MAYP is involved in regulation of the actin cytoskeleton is appealing because of the presence of both the FCH domain and regions sharing sequence similarity with known actin-binding domains and because of the rapid reorganization of actin observed in response to CSF-1 (18Boocock C.A. Jones G.E. Stanley E.R. Pollard J.W. J. Cell Sci. 1989; 93: 447-456PubMed Google Scholar, 19Webb S.E. Pollard J.W. Jones G.E. J. Cell Sci. 1996; 109: 793-803PubMed Google Scholar). The FCH domain has been found to occur at the extreme NH2 terminus of the nonreceptor tyrosine kinase FER, the Fujinami Sarcoma virus Fes/Fps family of proto-oncogene products, the RhoGAP protein p115, mouse proteins h74, and the growth arrest-specific gene product as well as two gene products fromCaenorhabditis elegans (FO9E10.9 and F45E1.7) and one fromS. cerevisiae. Several of these proteins have potential roles in organizing Rho proteins and the actin cytoskeleton. It has been suggested that the FCH domains may bind functionally related target molecules (25Aspenström P. Curr. Biol. 1997; 7: 479-487Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar). The coiled coil domain of MAYP is highly conserved with the central coiled coil domain of PST PIP (67% identity). These domains are also rich in lysine and arginine residues and resemble sequences present in several actin-binding proteins (16Vandekerckhove J. Curr. Opin. Cell Biol. 1990; 2: 41-50Crossref PubMed Scopus (124) Google Scholar,17Friederick E. Vancompernolle K. Huet C. Goethals M. Finidori J. Vandekerckhove J. Louvard D. Cell. 1992; 70: 81-92Abstract Full Text PDF PubMed Scopus (141) Google Scholar), including paramyosin, myosin heavy chain, and troponin. While PST PIP has not been reported to bind actin, its function is intimately involved in the regulation of F-actin. Thus the association of MAYP with F-actin and its close relationship to PST PIP are intriguing, particularly in view of the rapid reorganization of the cytoskeleton observed in response to CSF-1, that follows MAYP tyrosine phosphorylation. Obviously, it will be important to identify the PTP(s) and kinase(s) that regulate MAYP tyrosine phosphorylation, the mechanism by which MAYP associates with actin and its functional role in the CSF-1 response of macrophages. We thank Dr. Rafael Fernandez for advice and help with the cloning and expression of MAYP and various members of the laboratory (past and present) who assisted in the preparation of cell fractions. The sequencing was performed at the Laboratory of Macromolecular Analysis of the Albert Einstein College of Medicine. We thank Yuan Shi for handling of the samples and for help in the interpretation of the data." @default.
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W2061002918 title "A Novel Macrophage Actin-associated Protein (MAYP) Is Tyrosine-phosphorylated following Colony Stimulating Factor-1 Stimulation" @default.
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