c-Abl is activated by growth factors and Src family kinases and has a role in the cellular response to PDGF.
The c-Abl tyrosine kinase localizes to the cytoplasm and plasma membrane in addition to the nucleus. However, there is little information regarding a role for c-Abl in the cytoplasm/plasma membrane compartments. Here we report that a membrane pool of c-Abl is activated by the growth factors PDGF and EGF in fibroblasts. The pattern and kinetics of activation are similar to growth factor activation of Src family kinases. To determine whether a link existed between activation of c-Abl and members of the Src family, we examined c-Abl kinase activity in cells that expressed oncogenic Src proteins. We found that c-Abl kinase activity was increased by 10- to 20-fold in these cells, and that Src and Fyn kinases directly phosphorylated c-Abl in vitro. Furthermore, overexpression of wild-type Src potentiated c-Abl activation by growth factors, and a kinase-inactive form of Src reduced this activation, showing that Abl activation by growth factors occurs at least in part via activation of Src kinases. Significantly, we show that c-Abl has a functional role in the morphological response to PDGF. Whereas PDGF treatment of serum-starved wild-type mouse embryo fibroblasts resulted in distinct linear or circular/dorsal membrane ruffling, c-Abl-null cells demonstrated dramatically reduced ruffling in response to PDGF, which was rescued by physiological re-expression of c-Abl. These data identify c-Abl as a downstream target of activated receptor tyrosine kinases and Src family kinases, and show for the first time that c-Abl functions in the cellular response to growth factors.
Plattner
R
R
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710 USA.
Kadlec
L
L
DeMali
K A
KA
Kazlauskas
A
A
Pendergast
A M
AM
D016475:3T3 Cells; D000199:Actins / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D003599:Cytoskeleton / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D006133:Growth Substances / Q000494:pharmacology; D006801:Humans; D051379:Mice; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000378:metabolism*; D011233:Precipitin Tests; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism* / Q000502:physiology; D051381:Rats; D013997:Time Factors; D014407:Tumor Cells, Cultured; D019061:src-Family Kinases / Q000494:pharmacology
D000199:Actins; D006133:Growth Substances; D010982:Platelet-Derived Growth Factor; D016315:Proto-Oncogene Proteins c-abl; D019061:src-Family Kinases