Cables enhances cdk2 tyrosine 15 phosphorylation by Wee1, inhibits cell growth, and is lost in many human colon and squamous cancers.
Cyclin-dependent kinase 2 (cdk2) is a small serine/threonine kinase that regulates cell cycle progression. Cdk2 activity is tightly controlled by several mechanisms, including phosphorylation and dephosphorylation events. Cables is a recently described novel cdk-interacting protein. In proliferating cells, Cables was predominantly localized in the nucleus by cell fractionation and immunostaining. Expression of Cables in HeLa cells inhibited cell growth and colony formation. Cables enhanced cdk2 tyrosine 15 phosphorylation by the Wee1 protein kinase, an inhibitory phosphorylation, which led to decreased cdk2 kinase activity. The gene encoding Cables is located on human chromosome 18q11-12, a site that is frequently lost in squamous, colon, and pancreas cancers. We found that Cables was strongly expressed in normal human epithelial cells including squamous and glandular mucosa. Breast and pancreatic cancers show strong Cables expression; however, loss of Cables expression was found in approximately 50-60% of primary colon and head and neck cancer specimens. Lack of Cables expression was associated with loss of heterozygosity on chromosome 18q11. The data provide evidence for a Cables-mediated interplay between cdk2 and Wee1 that leads to inhibition of cell growth. Conversely, loss of Cables may cause uncontrolled cell growth and enhance tumor formation.
Wu
C L
CL
Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston 02114, USA.
Kirley
S D
SD
Xiao
H
H
Chuang
Y
Y
Chung
D C
DC
Zukerberg
L R
LR
D000818:Animals; D042846:CDC2-CDC28 Kinases; D019556:COS Cells; D002294:Carcinoma, Squamous Cell / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D018797:Cell Cycle Proteins; D002887:Chromosomes, Human, Pair 18; D003110:Colonic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D016213:Cyclins; D018076:DNA, Complementary / Q000235:genetics / Q000378:metabolism; D006131:Growth Inhibitors / Q000096:biosynthesis / Q000502:physiology; D006367:HeLa Cells; D006258:Head and Neck Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D051379:Mice; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000502:physiology; D010750:Phosphoproteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D014162:Transfection; D014443:Tyrosine / Q000378:metabolism
C486568:CABLES1 protein, human; C411580:Cables1 protein, mouse; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D016213:Cyclins; D018076:DNA, Complementary; D006131:Growth Inhibitors; D009687:Nuclear Proteins; D010750:Phosphoproteins; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; C499349:WEE1 protein, human; C499348:Wee1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; C495893:Cdk2 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases