J Biol Chem, Vol. 274, Issue 22, 15694-15700, May 28, 1999

Morphological Transformation Induced by Activation of the Mitogen-activated Protein Kinase Pathway Requires Suppression of the T-type Ca²⁺ Channel

Matthew W. Strobeck, Masaru Okuda, Hiroshi Yamaguchi^§, Arnold Schwartz^§, and Kenji Fukasawa

From the  Department of Cell Biology and ^§ Institute of Molecular Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0521

Transformation of fibroblasts by various oncogenes, including ras, mos, and src accompanies with characteristic morphological changes from flat to round (or spindle) shapes. Such morphological change is believed to play an important role in establishing malignant characteristics of cancer cells. Activation of the mitogen-activated protein kinase (MAPK) pathway is a converging downstream event of transforming activities of many oncogene products commonly found in human cancers. Intracellular calcium is known to regulate cellular morphology. In fibroblasts, Ca²⁺ influx is primarily controlled by two types of Ca²⁺ channels (T- and L-types). Here, we report that the T-type current was specifically inhibited in cells expressing oncogenically activated Ras as well as gain-of-function mutant MEK (MAPK/extracellular signal-regulated kinase (ERK) kinase, a direct activator of MAPK), whereas treatment of ras-transformed cells with a MEK-specific inhibitor restored T-type Ca²⁺ channel activity. Using a T-type Ca²⁺ channel antagonist, we further found that suppression of the T-type Ca²⁺ channel by the activated MAPK pathway is a prerequisite event for the induction and/or maintenance of transformation-associated morphological changes.