Integrin alpha2 and extracellular signal-regulated kinase are functionally linked in highly malignant autocrine transforming growth factor-alpha-driven colon cancer cells.
Recently, we have shown that autocrine transforming growth factor-alpha (TGF-alpha) controls the expression of integrin alpha2, cell adhesion to collagen IV and motility in highly progressed HCT116 colon cancer cells (Sawhney, R. S., Zhou, G-H. K., Humphrey, L. E., Ghosh, P., Kreisberg, J. I., and Brattain, M. G. (2002) J. Biol. Chem. 277, 75-86). We now report that expression of basal integrin alpha2 and its biological effects are controlled by constitutive activation of the extracellular signal-regulated/mitogen-activated protein kinase (ERK/MAPK) pathway. Treatment of cells with selective mitogen-activated protein kinase kinase (MEK) inhibitors PD098059 and U0126 showed that integrin alpha2 expression, cell adhesion, and activation of ERK are inhibited in a parallel concentration-dependent fashion. Moreover, autocrine TGF-alpha-mediated epidermal growth factor receptor activation was shown to control the constitutive activation of the ERK/MAPK pathway, since neutralizing antibody to the epidermal growth factor receptor was able to block basal ERK activity. TGF-alpha antisense-transfected cells also showed attenuated activation of ERK. Using a real time electric cell impedance sensing technique, it was shown that ERK-dependent integrin alpha2-mediated cell micromotion signaling is controlled by autocrine TGF-alpha. Thus, this study implicates ERK/MAPK signaling activated by endogenous TGF-alpha as one of the mechanistic features controlling metastatic spread.
Sawhney
Rajinder S
RS
Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
Sharma
Bhavya
B
Humphrey
Lisa E
LE
Brattain
Michael G
MG
D002070:Butadienes / Q000494:pharmacology; D002867:Chromones / Q000494:pharmacology; D003110:Colonic Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D039421:Integrin alpha2 / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D009025:Morpholines / Q000494:pharmacology; D009570:Nitriles / Q000494:pharmacology; D016211:Transforming Growth Factor alpha / Q000502:physiology*; D014407:Tumor Cells, Cultured
D002070:Butadienes; D002867:Chromones; D004791:Enzyme Inhibitors; D005419:Flavonoids; D039421:Integrin alpha2; D009025:Morpholines; D009570:Nitriles; D016211:Transforming Growth Factor alpha; C113580:U 0126; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D020928:Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one