title: Physiological signals and oncogenesis mediated through Crk family adapter proteins.
abstract: The viral Crk oncogene (v-Crk) is known to induce sarcomas in chicken and its cellular homologs c-Crk I, c-Crk II, and Crk-like (CRKL) have been implicated in many signal transduction events. These include cell differentiation, cell migration, and the induced nonresponsiveness of T-cells to stimulation of the T-cell receptor (TCR), a state known as anergy. CRKL is also the most prominent substrate of the Bcr-Abl oncoprotein which causes human chronic myelogenous leukemias (CML). The modular composition of the Crk family adapters which largely consist of Src homology (SH2 and SH3) domains has prompted an intensive search for physiological and pathological upstream and downstream signalling partners which selectively bind to these adapters. Upstream proteins include various receptors and large multisite docking proteins, while several protein kinases and guanine nucleotide release proteins (GNRPs) have been suggested to function downstream of c-Crk and CRKL. Most Crk/CRKL SH2- and SH3-binding proteins contain several docking sites with considerable sequence similarity. Thus the binding requirements of Crk/CRKL SH2 and SH3 domains are now well defined, providing a basis for the design of small inhibitory molecules to block the function of these adapter proteins. The enzymatic cascades activated through Crk family adapters are only partially known, but stress kinases (SAPKs/JNKs) and the GTPase Rap1, as well as the B-Raf isoform of the Raf protein kinases, are affected in some systems. Several yet unidentified, highly selective Crk interacting proteins detectable in specific cell types remain to be studied. More detailed analyses of the enzymatic activities triggered through Crk-type adapters will also be crucial to fully define the signalling pathways controlled by this protein family.
authors: Laboratory of Molecular Oncology, MSZ-Institute for Medical Radiation and Cell Research, University Würzberg, Germany. stephan.feller@mail.uni-wuerzburg.de
authors: S M
authors: SM
authors: Feller
authors: G
authors: G
authors: Posern
authors: J
authors: J
authors: Voss
authors: C
authors: C
authors: Kardinal
authors: D
authors: D
authors: Sakkab
authors: J
authors: J
authors: Zheng
authors: B S
authors: BS
authors: Knudsen
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D002471:Cell Transformation, Neoplastic; D002645:Chickens; D017635:Clonal Anergy / Q000502:physiology; D016384:Consensus Sequence; D050719:Crk-Associated Substrate Protein; D016207:Cytokines / Q000502:physiology; D003598:Cytoskeletal Proteins / Q000502:physiology; D004789:Enzyme Activation; D016044:Fusion Proteins, bcr-abl / Q000502:physiology; D005786:Gene Expression Regulation; D006133:Growth Substances / Q000502:physiology; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000503:physiopathology; D008954:Models, Biological; D005810:Multigene Family; D050736:Oncogene Protein v-crk; D051419:Paxillin; D010750:Phosphoproteins / Q000502:physiology; D011494:Protein Kinases / Q000502:physiology; D011506:Proteins; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D050737:Proto-Oncogene Proteins c-crk; D011947:Receptors, Antigen, B-Cell / Q000502:physiology; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D050717:Retinoblastoma-Like Protein p130; D015682:Retroviridae Proteins, Oncogenic / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D018909:src Homology Domains
chemical_list: C493841:BCAR1 protein, human; D050719:Crk-Associated Substrate Protein; D016207:Cytokines; D003598:Cytoskeletal Proteins; D006133:Growth Substances; D050736:Oncogene Protein v-crk; C496061:PXN protein, human; D051419:Paxillin; D010750:Phosphoproteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D050737:Proto-Oncogene Proteins c-crk; D011947:Receptors, Antigen, B-Cell; D011948:Receptors, Antigen, T-Cell; D050717:Retinoblastoma-Like Protein p130; D015682:Retroviridae Proteins, Oncogenic; D011494:Protein Kinases; D016044:Fusion Proteins, bcr-abl