Endogenous cAbl regulates receptor endocytosis.
There are two key processes underlying ligand-induced receptor endocytosis: receptor ubiquitylation and remodeling of the actin cytoskeleton. Tyrosine kinases play critical roles in both receptor endocytosis and actin reorganization. Interestingly, members of the Abl family are the only known tyrosine kinases that possess an actin-binding domain and thus have the potential to directly regulate the actin cytoskeleton. However, the role of non-transforming cAbl in receptor endocytosis remains undefined. We report that cAbl promotes ligand-induced antigen receptor endocytosis in B lymphocytes. We show that pharmacologic inhibition or genetic deletion of cAbl causes a defect in tyrosine phosphorylation of the cytoskeletal adapter CrkII. cAbl inhibition or ablation also impairs Rac activation downstream of CrkII, as well as antigen receptor capping and endocytosis. Although phosphorylation of CrkII has been suggested to maintain it in a closed inactive conformation, we demonstrate that it is in fact essential for the activation of Rac. On the other hand, association of CrkII with cCbl, a key mediator of receptor ubiquitylation, does not require CrkII phosphorylation and is cAbl-independent. Phosphorylation of cCbl itself is also cAbl-independent. Our results thus indicate that CrkII links receptor engagement to cytoskeletal remodeling by coupling cCbl- and cAbl-mediated signaling pathways that cooperatively regulate ligand-induced receptor endocytosis.
The Wistar Institute, 3601 Spruce Street, Philadelphia, Pennsylvania 19104-4268, USA. mjacob@wistar.org
Michele
M
Jacob
Leslie A
LA
Todd
R Sonali
RS
Majumdar
Yingzhu
Y
Li
Ken-Ichi
K
Yamamoto
Ellen
E
Puré
D000199:Actins / Q000378:metabolism; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D001549:Benzamides; D002645:Chickens; D003599:Cytoskeleton; D004705:Endocytosis; D000068877:Imatinib Mesylate; D010879:Piperazines / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D016315:Proto-Oncogene Proteins c-abl / Q000172:deficiency / Q000276:immunology / Q000378:metabolism*; D050721:Proto-Oncogene Proteins c-cbl / Q000276:immunology / Q000378:metabolism; D050737:Proto-Oncogene Proteins c-crk / Q000276:immunology / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D020744:rac GTP-Binding Proteins / Q000276:immunology / Q000378:metabolism
D000199:Actins; D001549:Benzamides; D010879:Piperazines; D050737:Proto-Oncogene Proteins c-crk; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D050721:Proto-Oncogene Proteins c-cbl; D016315:Proto-Oncogene Proteins c-abl; D020744:rac GTP-Binding Proteins