Abstract
Carcinoma cells selected for their ability to migrate in vitro showed enhanced invasive properties in vivo. Associated with this induction of migration was the anchorage-dependent phosphorylation of p130CAS (Crk-associated substrate), leading to its coupling to the adaptor protein c-CrkII (Crk). In fact, expression of CAS or its adaptor protein partner Crk was sufficient to promote cell migration, and this depended on CAS tyrosine phosphorylation facilitating an SH2-mediated complex with Crk. Cytokine-stimulated cell migration was blocked by CAS lacking the Crk binding site or Crk containing a mutant SH2 domain. This migration response was characterized by CAS/Crk localization to membrane ruffles and blocked by the dominant-negative GTPase, Rac, but not Ras. Thus, CAS/Crk assembly serves as a "molecular switch" for the induction of cell migration and appears to contribute to the invasive property of tumors.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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COS Cells
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Cell Membrane / chemistry
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Cell Membrane / metabolism
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Cell Movement / drug effects
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Cell Movement / physiology*
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Crk-Associated Substrate Protein
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Extracellular Matrix / physiology
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GTP-Binding Proteins / chemistry
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GTP-Binding Proteins / metabolism
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Gene Expression / genetics
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Gene Expression / physiology
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Humans
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Hypoglycemic Agents / pharmacology
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Insulin / pharmacology
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Membrane Proteins / analysis
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Neoplasm Metastasis
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Pancreas / cytology
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Pancreas / pathology
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Pancreas / physiopathology
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Pancreatic Neoplasms / pathology
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Phosphoproteins / drug effects
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Phosphoproteins / genetics
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Phosphoproteins / metabolism*
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Phosphorylation
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Protein Binding
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Proteins*
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Proto-Oncogene Proteins / drug effects
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-crk
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Rabbits
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Retinoblastoma-Like Protein p130
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Tumor Cells, Cultured
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Tyrosine / metabolism
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rac GTP-Binding Proteins
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ras Proteins / chemistry
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ras Proteins / metabolism
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src Homology Domains
Substances
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BCAR1 protein, human
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Crk-Associated Substrate Protein
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Hypoglycemic Agents
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Insulin
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Membrane Proteins
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Phosphoproteins
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Proteins
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-crk
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Retinoblastoma-Like Protein p130
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Tyrosine
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GTP-Binding Proteins
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rac GTP-Binding Proteins
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ras Proteins