Evidence Mounts for Receptor-Independent Activation of Heterotrimeric G Proteins Normally in Vivo: Positioning of the Mitotic Spindle in C. Elegans

David R. Manning^*

Department of Pharmacology, University of Pennsylvania School of Medicine, 3620 Hamilton Walk, Philadelphia, PA 19104-6084, USA.

Summary: Examples of the activation of heterotrimeric G proteins in vivo by any means other than through activated cell surface receptors have been limited to pathophysiological phenomena. With the discovery of proteins apart from receptors that facilitate guanine nucleotide exchange and affect G protein subunit dissociation directly, however, the notion of receptor-independent modes of activation in normal circumstances has become a subject of great interest. Three recent publications, each focusing on G protein regulators (GPRs) in asymmetric positioning of the mitotic spindle in the early Caenorhabditis elegans embryo, provide substantial support for the likelihood of such a form of activation. The C. elegans proteins GPR-1 and GPR-2 each contain a G protein regulatory motif, which supports interaction with G_i-like subunits. Inactivation of the genes encoding GPR-1 and GPR-2 prevents the correct positioning of the mitotic spindle in the one- and two-cell embryo. This phenotype is identical to that achieved by inactivation of genes encoding the G subunits GOA-1 and GPA-16. Because signaling in the one- and two-cell embryos is "intrinsic," the data suggest a GPR-dependent, receptor-independent mode of G protein activation. The GPRs interact preferentially with the guanosine diphosphate (GDP)-bound form of G subunits, and the GPR motif per se exhibits GDP dissociation inhibitor activity. The actions of the GPRs imply that GDP•G•GPR is a key intermediate or effector in force generation relevant to mitotic spindle positioning.

*Corresponding author. Telephone, (215) 898-1775; fax, (215) 573-2236; e-mail, manning{at}pharm.med.upenn.edu

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