{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T11:08:51Z","timestamp":1778584131370,"version":"3.51.4"},"reference-count":47,"publisher":"American Society of Hematology","issue":"9","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2001,5,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Wiskott-Aldrich syndrome (WAS) and X-linked thrombocytopenia are caused by mutations of the WAS protein (WASP) gene. WASP may be involved in the regulation of podosome, an actin-rich dynamic cell adhesion structure formed by various types of cells. The molecular links between WASP and podosomes or other cell adhesion structures are unknown. Platelets express an SH2-SH3 adapter molecule, CrkL, that can directly associate with paxillin, which is localized in podosomes. The hypothesis that CrkL binds to WASP was, therefore, tested. Results from coprecipitation experiments using anti-CrkL and GST-fusion proteins suggest that CrkL binds to WASP through its SH3 domain and that the binding was not affected by WASP tyrosine phosphorylation. The binding of GST-fusion SH3 domain of PSTPIP1 in vitro was also not affected by WASP tyrosine phosphorylation, suggesting that the binding of the SH3 domains to WASP is not inhibited by tyrosine phosphorylation of WASP. Anti-CrkL also coprecipitates a 72-kd protein, which was identified as syk tyrosine kinase, critical for collagen induced-platelet activation. CrkL immunoprecipitates contain kinase-active syk, as evidenced by an in vitro kinase assay. Coprecipitation experiments using GST-fusion CrkL proteins suggest that both SH2 and SH3 domains of CrkL are involved in the binding of CrkL to syk. WASP, CrkL, syk, and paxillin-like Hic-5 incorporated to platelet cytoskeleton after platelet aggregation. Thus, CrkL is a novel molecular adapter for WASP and syk and may potentially transfer these molecules to the cytoskeleton through association with cytoskeletal proteins such as Hic-5.<\/jats:p>","DOI":"10.1182\/blood.v97.9.2633","type":"journal-article","created":{"date-parts":[[2002,7,27]],"date-time":"2002-07-27T12:46:47Z","timestamp":1027774007000},"page":"2633-2639","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":36,"title":["CrkL is an adapter for Wiskott-Aldrich syndrome protein and Syk"],"prefix":"10.1182","volume":"97","author":[{"given":"Atsushi","family":"Oda","sequence":"first","affiliation":[{"name":"From the Hokkaido Red Cross Blood Center, Sapporo, and the Department of Medicine and Blood Center, Keio University, Tokyo, Japan; the Department of Pediatrics, University of Washington, School of Medicine, Seattle, WA; and the Department of Molecular Oncology, Genentech, San Francisco, CA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hans D.","family":"Ochs","sequence":"additional","affiliation":[{"name":"From the Hokkaido Red Cross Blood Center, Sapporo, and the Department of Medicine and Blood Center, Keio University, Tokyo, Japan; the Department of Pediatrics, University of Washington, School of Medicine, Seattle, WA; and the Department of Molecular Oncology, Genentech, San Francisco, CA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laurence A.","family":"Lasky","sequence":"additional","affiliation":[{"name":"From the Hokkaido Red Cross Blood Center, Sapporo, and the Department of Medicine and Blood Center, Keio University, Tokyo, Japan; the Department of Pediatrics, University of Washington, School of Medicine, Seattle, WA; and the Department of Molecular Oncology, Genentech, San Francisco, CA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susan","family":"Spencer","sequence":"additional","affiliation":[{"name":"From the Hokkaido Red Cross Blood Center, Sapporo, and the Department of Medicine and Blood Center, Keio University, Tokyo, Japan; the Department of Pediatrics, University of Washington, School of Medicine, Seattle, WA; and the Department of Molecular Oncology, Genentech, San Francisco, CA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katsutoshi","family":"Ozaki","sequence":"additional","affiliation":[{"name":"From the Hokkaido Red Cross Blood Center, Sapporo, and the Department of Medicine and Blood Center, Keio University, Tokyo, Japan; the Department of Pediatrics, University of Washington, School of Medicine, Seattle, WA; and the Department of Molecular Oncology, Genentech, San Francisco, CA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mitsuhiro","family":"Fujihara","sequence":"additional","affiliation":[{"name":"From the Hokkaido Red Cross Blood Center, Sapporo, and the Department of Medicine and Blood Center, Keio University, Tokyo, Japan; the Department of Pediatrics, University of Washington, School of Medicine, Seattle, WA; and the Department of Molecular Oncology, Genentech, San Francisco, CA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Makoto","family":"Handa","sequence":"additional","affiliation":[{"name":"From the Hokkaido Red Cross Blood Center, Sapporo, and the Department of Medicine and Blood Center, Keio University, Tokyo, Japan; the Department of Pediatrics, University of Washington, School of Medicine, Seattle, WA; and the Department of Molecular Oncology, Genentech, San Francisco, CA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kenji","family":"Ikebuchi","sequence":"additional","affiliation":[{"name":"From the Hokkaido Red Cross Blood Center, Sapporo, and the Department of Medicine and Blood Center, Keio University, Tokyo, Japan; the Department of Pediatrics, University of Washington, School of Medicine, Seattle, WA; and the Department of Molecular Oncology, Genentech, San Francisco, CA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hisami","family":"Ikeda","sequence":"additional","affiliation":[{"name":"From the Hokkaido Red Cross Blood Center, Sapporo, and the Department of Medicine and Blood Center, Keio University, Tokyo, Japan; the Department of Pediatrics, University of Washington, School of Medicine, Seattle, WA; and the Department of Molecular Oncology, Genentech, San Francisco, 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gene.","volume":"86","author":"Zhu","year":"1995","journal-title":"Blood."},{"key":"2020021219221901200_B4","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1146\/annurev.immunol.17.1.905","article-title":"The Wiskott-Aldrich syndrome protein (WASP): roles in signaling and cytoskeletal organization.","volume":"17","author":"Snapper","year":"1999","journal-title":"Annu Rev Immunol."},{"key":"2020021219221901200_B5","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1016\/S0167-5699(98)01350-4","article-title":"Is Wiskott-Aldrich syndrome a cell trafficking disorder?","volume":"19","author":"Thrasher","year":"1998","journal-title":"Immunol Today."},{"key":"2020021219221901200_B6","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/S0962-8924(98)01411-1","article-title":"Waltzing with WASP.","volume":"9","author":"Ramesh","year":"1999","journal-title":"Trends Cell Biol."},{"key":"2020021219221901200_B7","doi-asserted-by":"crossref","first-page":"1347","DOI":"10.1016\/S0960-9822(98)00015-3","article-title":"Scar1 and the related Wiskott-Aldrich syndrome protein, WASP, regulate the actin cytoskeleton through the Arp2\/3 complex.","volume":"8","author":"Machesky","year":"1998","journal-title":"Curr Biol."},{"key":"2020021219221901200_B8","doi-asserted-by":"crossref","first-page":"15212","DOI":"10.1021\/bi991843+","article-title":"Influence of the C terminus of Wiskott-Aldrich syndrome protein (WASp) and the Arp2\/3 complex on actin polymerization.","volume":"38","author":"Higgs","year":"1999","journal-title":"Biochemistry."},{"key":"2020021219221901200_B9","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/S0960-9822(02)00423-2","article-title":"Two GTPases, Cdc42 and Rac, bind directly to a protein implicated in the immunodeficiency disorder Wiskott-Aldrich 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protein.","volume":"54","author":"ten Hoeve","year":"1994","journal-title":"Cancer Res."},{"key":"2020021219221901200_B29","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1038\/sj.leu.2401010","article-title":"Role of the adapter protein CRKL in signal transduction of normal hematopoietic and BCR\/ABL-transformed cells.","volume":"12","author":"Sattler","year":"1998","journal-title":"Leukemia."},{"key":"2020021219221901200_B30","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1002\/(SICI)1097-4652(199812)177:4<535::AID-JCP5>3.0.CO;2-E","article-title":"Physiological signals and oncogenesis mediated through Crk family adapter proteins.","volume":"177","author":"Feller","year":"1988","journal-title":"J Cell Physiol."},{"key":"2020021219221901200_B31","doi-asserted-by":"crossref","first-page":"2277","DOI":"10.1016\/S0021-9258(18)53767-4","article-title":"Protein-tyrosine kinase p72syk is activated by thrombin and is negatively regulated through Ca2+ mobilization in platelets.","volume":"268","author":"Taniguchi","year":"1993","journal-title":"J Biol Chem."},{"key":"2020021219221901200_B32","doi-asserted-by":"crossref","first-page":"32796","DOI":"10.1016\/S0021-9258(20)30061-2","article-title":"Translocation of p72syk to the cytoskeleton in thrombin-stimulated platelets.","volume":"269","author":"Tohyama","year":"1994","journal-title":"J Biol Chem."},{"key":"2020021219221901200_B33","doi-asserted-by":"crossref","first-page":"2181","DOI":"10.1242\/jcs.111.15.2181","article-title":"Recruitment of the LIM protein hic-5 to focal contacts of human platelets.","volume":"111","author":"Hagmann","year":"1998","journal-title":"J Cell Sci."},{"key":"2020021219221901200_B34","doi-asserted-by":"crossref","first-page":"2943","DOI":"10.1182\/blood.V95.9.2943.009k17_2943_2946","article-title":"Wiskott-Aldrich syndrome protein is necessary for efficient IgG-mediated phagocytosis.","volume":"95","author":"Lorenzi","year":"2000","journal-title":"Blood."},{"key":"2020021219221901200_B35","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1038\/35008673","article-title":"Involvement of the Arp2\/3 complex in phagocytosis mediated by Fc\u03b3R or CR3.","volume":"2","author":"May","year":"2000","journal-title":"Nat Cell Biol."},{"key":"2020021219221901200_B36","doi-asserted-by":"crossref","first-page":"3713","DOI":"10.1182\/blood.V93.11.3713","article-title":"CrkL activates integrin-mediated hematopoietic cell adhesion through the guanine nucleotide exchange factor C3G.","volume":"93","author":"Arai","year":"1999","journal-title":"Blood."},{"key":"2020021219221901200_B37","doi-asserted-by":"crossref","first-page":"37525","DOI":"10.1074\/jbc.274.53.37525","article-title":"The adapter protein crkl links cbl to C3G after integrin ligation and enhances cell migration.","volume":"274","author":"Uemura","year":"1999","journal-title":"J Biol 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domains.","volume":"15","author":"Rivero-Lezcano","year":"1995","journal-title":"Mol Cell Biol."},{"key":"2020021219221901200_B41","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1182\/blood.V92.2.443","article-title":"Erythropoietin induces tyrosine phosphorylation of Jak2, STAT5A, and STAT5B in primary cultured human erythroid precursors.","volume":"92","author":"Oda","year":"1998","journal-title":"Blood."},{"key":"2020021219221901200_B42","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1074\/jbc.274.2.571","article-title":"Activation of a CrkL-stat5 signaling complex by type I interferons.","volume":"274","author":"Fish","year":"1999","journal-title":"J Biol Chem."},{"key":"2020021219221901200_B43","doi-asserted-by":"crossref","first-page":"21519","DOI":"10.1074\/jbc.274.31.21519","article-title":"T cell activation stimulates the association of enzymatically active tyrosine-phosphorylated ZAP-70 with the Crk adapter 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