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Vol. 10, Issue 9, 2829-2845, September 1999
and
*Department of Biology, Center for Molecular Genetics, University
of California, San Diego, La Jolla, California 92093-0634;
We have identified a novel Ras-interacting protein from
Dictyostelium, RIP3, whose function is required for both
chemotaxis and the synthesis and relay of the cyclic AMP (cAMP)
chemoattractant signal. rip3 null cells are unable to
aggregate and lack receptor activation of adenylyl cyclase but are
able, in response to cAMP, to induce aggregation-stage,
postaggregative, and cell-type-specific gene expression in suspension
culture. In addition, rip3 null cells are unable to
properly polarize in a cAMP gradient and chemotaxis is highly impaired.
We demonstrate that cAMP stimulation of guanylyl cyclase, which is
required for chemotaxis, is reduced ~60% in rip3 null
cells. This reduced activation of guanylyl cyclase may account, in
part, for the defect in chemotaxis. When cells are pulsed with cAMP for
5 h to mimic the endogenous cAMP oscillations that occur in
wild-type strains, the cells will form aggregates, most of which,
however, arrest at the mound stage. Unlike the response seen in
wild-type strains, the rip3 null cell aggregates that
form under these experimental conditions are very small, which is
probably due to the rip3 null cell chemotaxis defect. Many of the phenotypes of the rip3 null cell, including
the inability to activate adenylyl cyclase in response to cAMP and
defects in chemotaxis, are very similar to those of strains carrying a
disruption of the gene encoding the putative Ras exchange factor AleA.
We demonstrate that aleA null cells also exhibit a
defect in cAMP-mediated activation of guanylyl cyclase similar to that
of rip3 null cells. A double-knockout mutant
(rip3/aleA null cells) exhibits a further reduction in
receptor activation of guanylyl cyclase, and these cells display almost
no cell polarization or movement in cAMP gradients. As RIP3
preferentially interacts with an activated form of the
Dictyostelium Ras protein RasG, which itself is
important for cell movement, we propose that RIP3 and AleA are
components of a Ras-regulated pathway involved in integrating
chemotaxis and signal relay pathways that are essential for aggregation.
Department of Biological Chemistry, Johns Hopkins
University School of Medicine, Baltimore, Maryland 21205; and
Department of Biochemistry, Birmingham University,
Birmingham B15 2TT, United Kingdom
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