Association of the Cas-like molecule HEF1 with CrkL following integrin and antigen receptor signaling in human B-cells: potential relevance to neoplastic lymphohematopoietic cells.
CrkL, a cellular homologue of the v-crk oncogene, belongs to the family of adaptor proteins, containing SH2 and SH3 domains, but no catalytic domain. Stimulation of normal B-cells and B-cell lines through beta1 integrin or - cell antigen receptor (BCR) promoted the association of CrkL with a set of 105-130 kD tyrosine phosphorylated substrates. The principal substrate is a recently identified molecule known as p105HEF1 (HEF1), which is highly homologous to p130Cas (Cas), the major tyrosine-phosphorylated protein detected in fibroblasts after transformation by v-crk. Immunodepletion studies indicated that all the tyrosine phosphorylated HEF1 or Cas was complexed with CrkL. Furthermore, the guanine nucleotide exchange factor C3G, which is thought to be involved in the regulation of the ras pathway and constitutively binds to the C-terminal SH3 domain of CrkL, could be detected in HEF1 immunoprecipitates. Therefore, CrkL is involved in the formation of a HEF1-CrkL-C3G ternary complex in B-cells, suggesting that it is likely to play an important role, allowing the propagation of the stimulation initiated by both BCR and beta1 integrin ligation.
Astier
A
A
Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Philadelphia, PA, USA.
Manié
S N
SN
Law
S F
SF
Canty
T
T
Haghayghi
N
N
Druker
B J
BJ
Salgia
R
R
Golemis
E A
EA
Freedman
A S
AS
D048868:Adaptor Proteins, Signal Transducing; D001402:B-Lymphocytes / Q000378:metabolism* / Q000473:pathology; D002471:Cell Transformation, Neoplastic; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D018909:src Homology Domains
D048868:Adaptor Proteins, Signal Transducing; C082869:CRKL protein; D019012:Integrin beta1; C099942:NEDD9 protein, human; D009687:Nuclear Proteins; D010750:Phosphoproteins; D011947:Receptors, Antigen, B-Cell