The Cbl proteins are binding partners for the Cool/Pix family of p21-activated kinase-binding proteins.
Members of the Cool protein family contain SH3, Dbl, and pleckstrin homology domains and are binding partners for the p21-activated kinase (PAK). Using the yeast two-hybrid screen, we identified Cbl-b as a Cool family binding partner. We co-immunoprecipitated endogenous Cool and Cbl-b from a variety of breast cancer cell lines. The Cool-Cbl-b interaction requires the SH3 domain of Cool and competes with the binding of PAK to Cool proteins. Expression of Cbl-b effectively blocks the ability of Cool-2 to stimulate PAK, thus providing an additional mechanism, aside from catalyzing receptor ubiquitination, by which Cbl-b acts as a negative regulator for signaling activities requiring PAK activation.
Flanders
James A
JA
Department of Molecular Medicine, Baker Laboratory, Cornell University, Veterinary Medical Center, Ithaca, NY 14853, USA.
Feng
Qiyu
Q
Bagrodia
Shubha
S
Laux
Maria T
MT
Singavarapu
Avinash
A
Cerione
Richard A
RA
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D001667:Binding, Competitive; D001943:Breast Neoplasms / Q000378:metabolism; D019556:COS Cells; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D050721:Proto-Oncogene Proteins c-cbl; D064067:Rho Guanine Nucleotide Exchange Factors; D014407:Tumor Cells, Cultured; D020798:Two-Hybrid System Techniques; D044767:Ubiquitin-Protein Ligases; D054462:p21-Activated Kinases; D018909:src Homology Domains / Q000502:physiology
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D020662:Guanine Nucleotide Exchange Factors; C576609:PIX protein, human; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D064067:Rho Guanine Nucleotide Exchange Factors; C492211:CBLB protein, human; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; D017346:Protein Serine-Threonine Kinases; D054462:p21-Activated Kinases; C067419:CBL protein, human