Hematopoietic progenitor kinase 1 (HPK1) is implicated in signaling downstream of the T cell receptor. Its non-catalytic, C-terminal half contains several prolinerich motifs, which have been shown to interact with different SH3 domain-containing adaptor proteins in vitro. One of these, Mona/Gads, was also shown to bind HPK1 in mouse T cells in vivo. The region of HPK1 that binds to the Mona/Gads C-terminal SH3 domain has been mapped and shows only very limited similarity to a recently identified high affinity binding motif in SLP-76, another T-cell adaptor. Using isothermal titration calorimetry and x-ray crystallography, the binding of the HPK1 motif to Mona/Gads SH3C has now been characterized in molecular detail. The results indicate that although charge interactions through an RXXK motif are essential for complex formation, a PXXP motif in HPK1 strongly complements binding. This unexpected binding mode therefore differs considerably from the previously described interaction of Mona/Gads SH3C with SLP-76. The crystal structure of the complex highlights the great versatility of SH3 domains, which allows interactions with very different proteins. This currently limits our ability to categorize SH3 binding properties by simple rules. Hematopoietic progenitor kinase 1 (HPK1) is implicated in signaling downstream of the T cell receptor. Its non-catalytic, C-terminal half contains several prolinerich motifs, which have been shown to interact with different SH3 domain-containing adaptor proteins in vitro. One of these, Mona/Gads, was also shown to bind HPK1 in mouse T cells in vivo. The region of HPK1 that binds to the Mona/Gads C-terminal SH3 domain has been mapped and shows only very limited similarity to a recently identified high affinity binding motif in SLP-76, another T-cell adaptor. Using isothermal titration calorimetry and x-ray crystallography, the binding of the HPK1 motif to Mona/Gads SH3C has now been characterized in molecular detail. The results indicate that although charge interactions through an RXXK motif are essential for complex formation, a PXXP motif in HPK1 strongly complements binding. This unexpected binding mode therefore differs considerably from the previously described interaction of Mona/Gads SH3C with SLP-76. The crystal structure of the complex highlights the great versatility of SH3 domains, which allows interactions with very different proteins. This currently limits our ability to categorize SH3 binding properties by simple rules. Hematopoietic progenitor kinase 1 (HPK1 1The abbreviations used are: HPK1, hematopoietic progenitor kinase 1; MAP, mitogen-activated protein; MAP4K, MAP kinase kinase kinase kinase; GCK, germinal center kinase; JNK, c-Jun N-terminal kinase; ITC, isothermal titration calorimetry; PPII, polyproline type II. ; Human Genome Organization gene symbol MAP4K1) is a member of the germinal center kinase (GCK) family within the large superfamily of STE20 and p21-activated kinases (Refs. 1Dan I. Watanabe N.M. Kusumi A. Trends Cell Biol. 2001; 11: 220-230Abstract Full Text Full Text PDF PubMed Scopus (514) Google Scholar and 2Sells M.A. Chernoff J. Trends in Cell Biology. 1997; 7: 162-167Abstract Full Text PDF PubMed Scopus (265) Google Scholar). As its name indicates, HPK1 expression is prominent in hematopoietic cells. Initial cloning reports implicated HPK1 in the activation of stress kinases (SAPKs/JNKs) (3Hu M.C. Qiu W.R. Wang X. Meyer C.F. Tan T.H. Genes Dev. 1996; 10: 2251-2264Crossref PubMed Scopus (195) Google Scholar, 4Kiefer F. Tibbles L.A. Anafi M. Janssen A. Zanke B.W. Lassam N. Pawson T. Woodgett J.R. Iscove N.N. EMBO J. 1996; 15: 7013-7025Crossref PubMed Scopus (200) Google Scholar). Since then, HPK1 activity has been associated with lymphocyte antigen receptor signaling (BCR, TCR; Refs. 5Liu S.K. Smith C.A. Arnold R. Kiefer F. McGlade C.J. J. Immunol. 2000; 165: 1417-1426Crossref PubMed Scopus (57) Google Scholar, 6Ma W. Xia C. Ling P. Qiu M. Luo Y. Tan T.H. Liu M. Oncogene. 2001; 20: 1703-1714Crossref PubMed Scopus (44) Google Scholar, 7Tsuji S. Okamoto M. Yamada K. Okamoto N. Goitsuka R. Arnold R. Kiefer F. Kitamura D. J. Exp. Med. 2001; 194: 529-539Crossref PubMed Scopus (55) Google Scholar, 8Kiefer F. Vogel W.F. Arnold R. Transpl. Immunol. 2002; 9: 69-82Crossref PubMed Scopus (18) Google Scholar, 9Han J. Kori R. Shui J.W. Chen Y.R. Yao Z. Tan T.H. J. Biol. Chem. 2003; 278: 52195-52202Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar) and in signaling induced by transforming growth factor-β (10Wang W. Zhou G. Hu M.C. Yao Z. Tan T.H. J. Biol. Chem. 1997; 272: 22771-22775Abstract Full Text Full Text PDF PubMed Scopus (163) Google Scholar, 11Zhou G. Lee S.C. Yao Z. Tan T.H. J. Biol. Chem. 1999; 274: 13133-13138Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar). It has also been shown that physiological concentrations of prostaglandin E2 raise HPK1 kinase activity in T cells and myeloid cells by a yet undefined mechanism, possibly leading to the suppression of fos gene transcription (12Sawasdikosol S. Russo K.M. Burakoff S.J. Blood. 2003; 101: 3687-3689Crossref PubMed Scopus (24) Google Scholar). In addition, a single report suggests a role for HPK1 in erythropoietin-induced signaling of two cell lines (13Nagata Y. Kiefer F. Watanabe T. Todokoro K. Blood. 1999; 93: 3347-3354Crossref PubMed Google Scholar), but this finding remains unconfirmed for primary erythroid progenitor cells. HPK1 is presumed to act as a MAP4K (MAP kinase kinase kinase kinase). Its potential substrates include the mixed lineage kinase MLK3, the mitogenic kinase MEKK1, the transforming growth factor-β activated kinase TAK1 (8Kiefer F. Vogel W.F. Arnold R. Transpl. Immunol. 2002; 9: 69-82Crossref PubMed Scopus (18) Google Scholar), and also c-Jun. 2E. K. Schmidt and S. M. Feller, unpublished data. Furthermore, HPK1 is activated by caspase cleavage (14Chen Y.R. Meyer C.F. Ahmed B. Yao Z. Tan T.H. Oncogene. 1999; 18: 7370-7377Crossref PubMed Scopus (67) Google Scholar, 15Arnold R. Liou J. Drexler H.C. Weiss A. Kiefer F. J. Biol. Chem. 2001; 276: 14675-14684Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar) and functions as a regulator of NFκB signaling (15Arnold R. Liou J. Drexler H.C. Weiss A. Kiefer F. J. Biol. Chem. 2001; 276: 14675-14684Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar, 16Hu M.C. Wang Y. Qiu W.R. Mikhail A. Meyer C.F. Tan T.H. Oncogene. 1999; 18: 5514-5524Crossref PubMed Scopus (48) Google Scholar). Despite these reports, the in vivo functions and signaling pathways of HPK1 remain only marginally defined. HPK1(-/-) mice have been generated by targeted gene disruption but exhibit no obvious phenotype. 3F. Kiefer, personal communication. This may not be entirely surprising, given that HPK1 is just one member of a family of similar kinases with hematopoietic expression (1Dan I. Watanabe N.M. Kusumi A. Trends Cell Biol. 2001; 11: 220-230Abstract Full Text Full Text PDF PubMed Scopus (514) Google Scholar, 2Sells M.A. Chernoff J. Trends in Cell Biology. 1997; 7: 162-167Abstract Full Text PDF PubMed Scopus (265) Google Scholar). Close relatives with overlapping expression patterns include GCK, kinase homologous to SPS1/STE20 (syn. GCKR), HPK1/GCK-like kinase (named NIK in mice) and germinal center-like kinase. The targeted disruption of multiple GCK family kinase genes in mice may eventually shed more light on HPK1 functions. Physical interactions of HPK1 with other intracellular proteins in vitro and in vivo have been reported in numerous studies. The T-cell adaptor SLP-76 and its B-cell relative BLNK, also known as SLP-65 or BASH, are functionally important interaction partners of HPK1 and crucial in the signal transmission of TCR and BCR, respectively (5Liu S.K. Smith C.A. Arnold R. Kiefer F. McGlade C.J. J. Immunol. 2000; 165: 1417-1426Crossref PubMed Scopus (57) Google Scholar, 7Tsuji S. Okamoto M. Yamada K. Okamoto N. Goitsuka R. Arnold R. Kiefer F. Kitamura D. J. Exp. Med. 2001; 194: 529-539Crossref PubMed Scopus (55) Google Scholar, 17Liou J. Kiefer F. Dang A. Hashimoto A. Cobb M.H. Kurosaki T. Weiss A. Immunity. 2000; 12: 399-408Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar, 18Sauer K. Liou J. Singh S.B. Yablonski D. Weiss A. Perlmutter R.M. J. Biol. Chem. 2001; 276: 45207-45216Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar). After receptor activation, SLP-76 and BLNK bind via their SH2 domains to the phosphorylated tyrosine 397 of human HPK1 (18Sauer K. Liou J. Singh S.B. Yablonski D. Weiss A. Perlmutter R.M. J. Biol. Chem. 2001; 276: 45207-45216Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar). Other protein complexes are formed via four proline-rich motifs in the non-catalytic region of HPK1. SH3 domain-containing adaptors, including Crk, CRKL, Grb2, Nck, Mona/Gads (syn. Grap-2, GrpL, Grf40, GRID), and HIP-55 have been shown to bind HPK1 (5Liu S.K. Smith C.A. Arnold R. Kiefer F. McGlade C.J. J. Immunol. 2000; 165: 1417-1426Crossref PubMed Scopus (57) Google Scholar, 6Ma W. Xia C. Ling P. Qiu M. Luo Y. Tan T.H. Liu M. Oncogene. 2001; 20: 1703-1714Crossref PubMed Scopus (44) Google Scholar, 9Han J. Kori R. Shui J.W. Chen Y.R. Yao Z. Tan T.H. J. Biol. Chem. 2003; 278: 52195-52202Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar, 19Anafi M. Kiefer F. Gish G.D. Mbamalu G. Iscove N.N. Pawson T. J. Biol. Chem. 1997; 272: 27804-27811Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar, 20Ensenat D. Yao Z. Wang X.S. Kori R. Zhou G. Lee S.C. Tan T.H. J. Biol. Chem. 1999; 274: 33945-33950Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar, 21Oehrl W. Kardinal C. Ruf S. Adermann K. Groffen J. Feng G.S. Blenis J. Tan T.H. Feller S.M. Oncogene. 1998; 17: 1893-1901Crossref PubMed Scopus (52) Google Scholar, 22Ling P. Yao Z. Meyer C.F. Wang X.S. Oehrl W. Feller S.M. Tan T.H. Mol. Cell. Biol. 1999; 19: 1359-1368Crossref PubMed Scopus (78) Google Scholar). Of these, Mona/Gads binding to HPK1 was clearly demonstrated in mouse T cells by co-immunoprecipitation of the endogenous proteins (5Liu S.K. Smith C.A. Arnold R. Kiefer F. McGlade C.J. J. Immunol. 2000; 165: 1417-1426Crossref PubMed Scopus (57) Google Scholar). The same study implicated the fourth proline-rich motif in the non-catalytic part of HPK1 as the binding region for Mona/Gads but did not provide details regarding the HPK1 residues crucial for high affinity binding. We and others have recently shown that the SH3C domain of Mona/Gads can interact with nanomolar affinity with a SLP-76 motif, which lacks a typical PXXP motif (23Liu Q. Berry D. Nash P. Pawson T. McGlade C.J. Li S.S. Mol. Cell. 2003; 11: 471-481Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar, 24Harkiolaki M. Lewitzky M. Gilbert R.J. Jones E.Y. Bourette R.P. Mouchiroud G. Sondermann H. Moarefi I. Feller S.M. EMBO J. 2003; 22: 2571-2582Crossref PubMed Scopus (95) Google Scholar). In this study, the interaction of HPK1 with Mona/Gads was initially analyzed by isothermal titration calorimetry (ITC). Subsequently, a suitable fragment of HPK1 in complex with Mona/Gads SH3C was crystallized and studied by x-ray crystallography. The structure of the Mona/Gads SH3C-HPK1 peptide complex was solved to 1.5-Å resolution. The data show that, different from the interaction of Mona/Gads SH3C with SLP-76, a PXXP motif, which is part of a polyproline type II is essential for complex of Mona/Gads SH3C and HPK1. and crystal the residues as for complex as as expression and of Mona/Gads SH3C as described previously M. Lewitzky M. Gilbert R.J. Jones E.Y. Bourette R.P. Mouchiroud G. Sondermann H. Moarefi I. Feller S.M. EMBO J. 2003; 22: 2571-2582Crossref PubMed Scopus (95) Google Scholar). The expression for is a of and of this protein was the same as for Mona/Gads The of the been previously in cell was as described previously M. Lewitzky M. Gilbert R.J. Jones E.Y. Bourette R.P. Mouchiroud G. Sondermann H. Moarefi I. Feller S.M. EMBO J. 2003; 22: 2571-2582Crossref PubMed Scopus (95) Google Scholar). on a of domain in was for and for with the to in and and was the the and of peptide and the an of The of was generated and in the Mona/Gads SH3C was mixed with the HPK1 peptide a with the of through and data on the also The structure was solved by molecular J. P. 1997; 276: PubMed Scopus Google Scholar) with as the The was the A. PubMed Scopus Google Scholar) and with D. 1997; PubMed Scopus Google II for of structure and as as of and as described previously M. Lewitzky M. Gilbert R.J. Jones E.Y. Bourette R.P. Mouchiroud G. Sondermann H. Moarefi I. Feller S.M. EMBO J. 2003; 22: 2571-2582Crossref PubMed Scopus (95) Google and cell in to the is the is the of the and is the the on of the data from in to the is the is the of the and is the the on of the from J. Google Scholar) in a of the in HPK1 for Mona/Gads SH3C the SH3C domain of Mona/Gads is the only domain of this adaptor known to protein complex of tyrosine have shown that the Mona/Gads SH3C domain binds with very high affinity to a motif from SLP-76 and that of the residues considerably to complex M. Lewitzky M. Gilbert R.J. Jones E.Y. Bourette R.P. Mouchiroud G. Sondermann H. Moarefi I. Feller S.M. EMBO J. 2003; 22: 2571-2582Crossref PubMed Scopus (95) Google Scholar). HPK1, which also binds to Mona/Gads of tyrosine lacks a motif the implicated region in HPK1 contains only an RXXK motif in the mouse protein and a motif in the human HPK1 proteins have a of residues N-terminal to the motif, which is not in SLP-76, and possibly to Mona/Gads SH3C binding. this to of the region in mouse and human HPK1 and analyzed for binding by to Mona/Gads SH3C with of and are typical for known SH3 of mouse HPK1 for SH3 domains binding to SH3 domains was analyzed by isothermal titration calorimetry as Mona/Gads SH3C and mouse and as proteins. no binding affinity for for two high affinity binding similar to The motif is to be crucial for in a The essential Mona/Gads SH3C binding region in mouse HPK1 was mapped by overlapping HPK1 of an is shown in a motif, was the with an affinity by in a through the motif as essential for mouse HPK1 binding to Mona/Gads SH3C As HPK1 has several proline-rich in the non-catalytic part of the In one study, human HPK1, a region different from the implicated in the mouse HPK1 has been as the binding for Mona/Gads SH3C W. Xia C. Ling P. Qiu M. Luo Y. Tan T.H. Liu M. Oncogene. 2001; 20: 1703-1714Crossref PubMed Scopus (44) Google Scholar). peptide was therefore also for binding to Mona/Gads SH3C by the affinity of this peptide was considerably that of and no with The Mona/Gads SH3C binding motif identified in mouse HPK1 clearly with the motif for binding of the N-terminal SH3 domain of the as previously in several G. J. Kardinal C. J. T. D. G. Wang B. G.D. S.K. C.A. Adermann K. H. Feller S.M. Oncogene. 1998; PubMed Scopus Google Scholar and to be and therefore with Mona/Gads for binding the affinity of the domain for two and was also only binding was although an with another peptide clearly that the domain is The the HPK1 that binds to Mona/Gads SH3C and the characterized SH3C binding motif in SLP-76 to the Mona/Gads SH3C-HPK1 peptide interaction by x-ray crystallography. of the Mona/Gads SH3C in with an from a complex of Mona/Gads SH3C with peptide and are in II. The structure of the complex was solved to 1.5-Å by molecular of the SH3 domain in complex with the HPK1 peptide is shown in The structure of the SH3C domain remains by HPK1 peptide the described previously M. Lewitzky M. Gilbert R.J. Jones E.Y. Bourette R.P. Mouchiroud G. Sondermann H. Moarefi I. Feller S.M. EMBO J. 2003; 22: 2571-2582Crossref PubMed Scopus (95) Google Scholar). The typical SH3 domain the same binding to the HPK1 peptide as in the of the SLP-76 peptide shown in although the interactions domain and peptide in this structure considerably from in the complex M. Lewitzky M. Gilbert R.J. Jones E.Y. Bourette R.P. Mouchiroud G. Sondermann H. Moarefi I. Feller S.M. EMBO J. 2003; 22: 2571-2582Crossref PubMed Scopus (95) Google Scholar). residues the HPK1 peptide in its from the SH3 domain residues by in the The within the peptide are a from residues to and a polyproline type II of residues to and the is also in the high affinity SLP-76 peptide described the within the HPK1 peptide is clearly for a Mona/Gads SH3C potential of the Mona/Gads SH3C with the in potential is in and potential is in of a HPK1 peptide and an SLP-76 peptide on the Mona/Gads SH3C The SLP-76 peptide structure is from structure in the HPK1 peptide are with and of the of interactions the HPK1 SH3C domain from the of the HPK1 peptide the residues not to although in a very interaction with to be the for peptide The of this in a formed by and the of the and a to the This interaction is by a from the of to the of the only a single the peptide to of The the of the HPK1 peptide on the domain is formed by residues and interactions in this region the of and to a in their for peptide binding. The of the of the from the of to the of the of and the of the peptide the SH3 and the of which this The interactions of and which the a of with residues of the Mona/Gads and of to and of and to and in a to that in the binding of the SLP-76 peptide to the same interaction M. Lewitzky M. Gilbert R.J. Jones E.Y. Bourette R.P. Mouchiroud G. Sondermann H. Moarefi I. Feller S.M. EMBO J. 2003; 22: 2571-2582Crossref PubMed Scopus (95) Google Scholar). In addition, the of not to SH3 domain binding the of the and residues of the the of the structure The C-terminal residues of not in protein and have no interaction with of the Mona/Gads residues in the The interactions only provide structure to this of the from binding with and in and the SH3 and HPK1 peptide identified in the crystal structure in by in clearly the residues in mouse HPK1 as important for Mona/Gads SH3C binding. This motif differs considerably from the previously identified motif from the SLP-76 protein M. Lewitzky M. Gilbert R.J. Jones E.Y. Bourette R.P. Mouchiroud G. Sondermann H. Moarefi I. Feller S.M. EMBO J. 2003; 22: 2571-2582Crossref PubMed Scopus (95) Google Scholar), although the RXXK motif is in mouse proteins. is from the human HPK1 that the can be with a only a single as a It is therefore not to binding partners of Mona/Gads of the SH3C-HPK1 with Other SH3 have previously reported the structure of a peptide in complex with Mona/Gads SH3C M. Lewitzky M. Gilbert R.J. Jones E.Y. Bourette R.P. Mouchiroud G. Sondermann H. Moarefi I. Feller S.M. EMBO J. 2003; 22: 2571-2582Crossref PubMed Scopus (95) Google Scholar). The and SH3C binding the and the RXXK motifs are in similar although the SLP-76 peptide lacks a its C-terminal region the same as the on the region of the SH3C The the are for the HPK1 peptide as with for the SLP-76 peptide and therefore not provide a simple for the in binding affinity of the SLP-76 the HPK1 peptide and and 24Harkiolaki M. Lewitzky M. Gilbert R.J. Jones E.Y. Bourette R.P. Mouchiroud G. Sondermann H. Moarefi I. Feller S.M. EMBO J. 2003; 22: 2571-2582Crossref PubMed Scopus (95) Google of the HPK1 peptide can be identified by of the which provide an of the of in the crystal structure of and This is by the residues of the which are not by binding to on the of the Mona/Gads The of by the of the two structure one and one is to which are with SH3 domain exhibit for of with the only marginally a with the Mona/Gads SH3C complex with an SLP-76 peptide is not to in data and crystal can the for the of the implicated in SH3C binding to a generated that the binding of the of the is residues of the SLP-76 peptide to SH3C residues of to a of the HPK1 residues not in binding. the relative of the region of be for by an induced on binding SH3C its N-terminal part not in complex The to be to SH3C binding. shows the large of but also in the that the Mona/Gads SH3C with the HPK1 and SLP-76 residues of the SH3 domain in to peptide binding. are also to residues within the Mona/Gads which are to the interaction with the SLP-76 peptide are part of two of the SH3 domain which to the of the HPK1 peptide only one SH3 domain within the which is not in the binding of the SLP-76 SH3 domains are protein interaction binding can via of their domain in K. R. H. D. EMBO J. 2002; PubMed Scopus Google Scholar), but a SH3 domain can also to only two of other SH3 interactions are with the Mona/Gads SH3C with the HPK1 The is the interaction of the SH3 domain from the adaptor protein with a peptide from the known as which binds with affinity T. T. T. T. K. Kitamura N. N. J. Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus (48) Google Scholar). We and others have previously shown that Mona/Gads SH3C can bind to the protein and from in vitro (23Liu Q. Berry D. Nash P. Pawson T. McGlade C.J. Li S.S. Mol. Cell. 2003; 11: 471-481Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar, 24Harkiolaki M. Lewitzky M. Gilbert R.J. Jones E.Y. Bourette R.P. Mouchiroud G. Sondermann H. Moarefi I. Feller S.M. EMBO J. 2003; 22: 2571-2582Crossref PubMed Scopus (95) Google Scholar), but have to a complex of the two proteins within cells. The peptide was very recently with the SH3 SH3 of the HPK1 peptide with the peptide shows that not only a in the RXXK region but that also similar on the SH3 domain SH3 domains are for to bind to Mona/Gads SH3C in vivo is not from a of the crystal and to be through and studies. The peptide is the peptide structure as in complex with As the peptide contains a motif that is crucial for binding. a motif is also in the HPK1 but its binding to is of the HPK1 peptide to the peptide shows a high of similarity with to peptide relative to the SH3 domains and also structure in the proline-rich the of the structure of in complex with a peptide and the Mona/Gads SH3C-HPK1 peptide structure a for the affinity binding of RXXK motifs to the of the are shown in and C. In the and of to of can no bind to the of the RXXK motif in the same as its Mona/Gads The of the to the binding to with the the for binding to the of the RXXK the affinity of this interaction is Furthermore, for the of the of the within although that not binding as shown by the high affinity Mona/Gads complex in which are M. Lewitzky M. Gilbert R.J. Jones E.Y. Bourette R.P. Mouchiroud G. Sondermann H. Moarefi I. Feller S.M. EMBO J. 2003; 22: 2571-2582Crossref PubMed Scopus (95) Google Scholar). by SH3 with of show that simple SH3 domain interactions with motifs of proteins can a of binding with more SH3 domains in the of SH3 complexes within cells on several other to and functionally protein include obvious as and of the expression of potential binding but of proteins can the binding of SH3 domains or (Refs. S.M. B. H. EMBO J. PubMed Scopus Google Scholar, H. C. Immunity. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, Lee G. P. B. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar, A. S. P. S. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar and protein complexes on the interaction of several SH3 other domains not only in binding but may also a great of binding In the of Mona/Gads, several complexes be on the of its known activation of the T-cell adaptor proteins as phosphorylated on multiple tyrosine This of several Mona/Gads a single via their SH2 domains, possibly several of HPK1 or SLP-76 that are to the Mona/Gads SH3C HPK1 and SLP-76 are also known to interact binding of the SLP-76 SH2 domain to a phosphorylated tyrosine on 18Sauer K. Liou J. Singh S.B. Yablonski D. Weiss A. Perlmutter R.M. J. Biol. Chem. 2001; 276: 45207-45216Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar), is that a complex of one of HPK1 to one of SLP-76 and two Mona/Gads may on in activated in cells. of a complex be through of Mona/Gads SH3C domains M. Lewitzky M. Gilbert R.J. Jones E.Y. Bourette R.P. Mouchiroud G. Sondermann H. Moarefi I. Feller S.M. EMBO J. 2003; 22: 2571-2582Crossref PubMed Scopus (95) Google Scholar). The potential of SLP-76 and HPK1 on via two Mona/Gads have for signal by molecular and are to the of signaling complexes in and other cells. results that is not a of simple that can be to of great as of to SH3 domain are very to single functionally important that are on only residues as the crucial motif the Mona/Gads SH3C binding in the HPK1 and SLP-76 proteins. The is of SH3 domains with as Mona/Gads and SH3 T. T. T. T. K. Kitamura N. N. J. Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus (48) Google Scholar). of results from one to another may also be limited given for the in mouse and human HPK1 was the was the the We for with M. for Human for with data and and peptide for numerous Janssen of for the of for to and Kiefer for for
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