The kinase-deficient Src acts as a suppressor of the Abl kinase for Cbl phosphorylation.
The kinase activity of Abl is known to be regulated by a putative trans-acting inhibitor molecule interacting with the Src homology (SH) 3 domain of Abl. Here we report that the kinase-deficient Src (SrcKD) directly inhibits the tyrosine phosphorylation of Cbl and other cellular proteins by Abl. We found that both the SH2 and SH3 domains of SrcKD are necessary for the suppressor activity toward the Abl kinase phosphorylating Cbl. To suppress the Cbl phosphorylation by Abl, the interaction between the SH3 domain of SrcKD and Cbl is required. This interaction between SrcKD and Cbl is regulated by a closed structure of Cbl. The binding of Abl to the extreme carboxyl-terminal region of Cbl unmasks the binding site of SrcKD to Cbl. This results in a ternary complex that inhibits the Abl-mediated phosphorylation of Cbl by steric hindrance. These results illustrate a mechanism by which the enzymatically inactive Src can exert a biological function in vivo.
Shishido
T
T
Laboratory of Molecular Oncology, The Rockefeller University, New York, NY 10021, USA.
Akagi
T
T
Ouchi
T
T
Georgescu
M M
MM
Langdon
W Y
WY
Hanafusa
H
H
D000595:Amino Acid Sequence; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000378:metabolism*; D016315:Proto-Oncogene Proteins c-abl / Q000502:physiology*; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; D018909:src Homology Domains; D019061:src-Family Kinases / Q000502:physiology*
D011518:Proto-Oncogene Proteins; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; D016315:Proto-Oncogene Proteins c-abl; D019061:src-Family Kinases