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Molecular and Cellular Biology, January 2004, p. 651-661, Vol. 24, No. 2
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.2.651-661.2004

Phosphorylation of Critical Serine Residues in Gem Separates Cytoskeletal Reorganization from Down-Regulation of Calcium Channel Activity

Y. Ward,1 B. Spinelli,1 M. J. Quon,2 H. Chen,3 S. R. Ikeda,3 and K. Kelly1*

Cell and Cancer Biology Branch, Center for Cancer Research, National Cancer Institute,1 Diabetes Unit, Lab of Clinical Investigation, National Center for Complementary and Alternative Medicine,2 Lab of Molecular Physiology, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland 208923

Received 4 September 2003/ Returned for modification 8 October 2003/ Accepted 23 October 2003

Gem is a small GTP-binding protein that has a ras-like core and extended chains at each terminus. The primary structure of Gem and other RGK family members (Rad, Rem, and Rem2) predicts a GTPase deficiency, leading to the question of how Gem functional activity is regulated. Two functions for Gem have been demonstrated, including inhibition of voltage-gated calcium channel activity and inhibition of Rho kinase-mediated cytoskeletal reorganization, such as stress fiber formation and neurite retraction. These functions for Gem have been ascribed to its interaction with the calcium channel ß subunit and Rho kinase ß, respectively. We show here that these functions are separable and regulated by distinct structural modifications to Gem. Phosphorylation of serines 261 and 289, located in the C-terminal extension, is required for Gem-mediated cytoskeletal reorganization, while GTP and possibly calmodulin binding are required for calcium channel inhibition. In addition to regulating cytoskeletal reorganization, phosphorylation of serine 289 in conjunction with serine 23 results in bidentate 14-3-3 binding, leading to increased Gem protein half-life. Evidence presented shows that phosphorylation of serine 261 is mediated via a cdc42/protein kinase C{zeta}-dependent pathway. These data demonstrate that phosphorylation of serines 261 and 289, outside the GTP-binding region of Gem, controls its inhibition of Rho kinase ß and associated changes in the cytoskeleton.

* Corresponding author. Mailing address: Building 10, Room 3B43, CCR, NCI, NIH, Bethesda, MD 20892. Phone: (301) 435-4652. Fax: (301) 435-4655. E-mail: kkelly{at}helix.nih.gov.

Molecular and Cellular Biology, January 2004, p. 651-661, Vol. 24, No. 2
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.2.651-661.2004




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