Mechanisms of regulation of cell adhesion and motility by insulin receptor substrate-1 in prostate cancer cells.
LNCaP cells are human prostatic cancer cells that have a frame-shift mutation of the tumor suppressor gene PTEN and do not express the insulin receptor substrate-1 (IRS-1), a major substrate of the type 1 insulin-like growth factor receptor (IGF-IR). Ectopic expression of IRS-1 in LNCaP cells increases cell adhesion and decreases cell motility by an IGF-I-independent mechanism. We show now that these effects of IRS-1 are accompanied by serine phosphorylation of IRS-1 and are inhibited by inhibitors of phosphatidylinositol 3-kinase (PI3K). We have confirmed the requirement for PI3K activity and serine phosphorylation by the use of IRS-1 mutants, expressed in LNCaP cells. Serine phosphorylation inhibits IGF-I-induced tyrosyl phosphorylation of IRS-1, which is restored by the expression of wild-type PTEN or by inhibition of PI3K activity. Finally, IRS-1 in LNCaP cells co-immunoprecipitates with integrin alpha 5 beta 1, and the association is again IGF-I-independent. We conclude that in LNCaP cells, IRS-1 is serine phosphorylated by PI3K, generating effects that are different, and even opposite, from those generated by IGF-I.
Reiss
K
K
Kimmel Cancer Center, Thomas Jefferson University, 624 Biology Life Science Building, 233 South 10th Street, Philadelphia, Pennsylvania, PA 19107, USA.
Wang
J Y
JY
Romano
G
G
Tu
X
X
Peruzzi
F
F
Baserga
R
R
D000230:Adenocarcinoma / Q000473:pathology / Q000503:physiopathology / Q000556:secondary; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement; D003094:Collagen / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D008297:Male; D009154:Mutation; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000473:pathology / Q000503:physiopathology* / Q000556:secondary; D011485:Protein Binding; D017469:Receptors, Fibronectin / Q000378:metabolism
D005353:Fibronectins; C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins; D017469:Receptors, Fibronectin; D003094:Collagen