A System of Counteracting Feedback Loops Regulates Cdc42p Activity during Spontaneous Cell Polarization

Abstract

Cellular polarization is often a response to distinct extracellular or intracellular cues, such as nutrient gradients or cortical landmarks. However, in the absence of such cues, some cells can still select a polarization axis at random. Positive feedback loops promoting localized activation of the GTPase Cdc42p are central to this process in budding yeast. Here, we explore spontaneous polarization during bud site selection in mutant yeast cells that lack functional landmarks. We find that these cells do not select a single random polarization axis, but continuously change this axis during the G1 phase of the cell cycle. This is reflected in traveling waves of activated Cdc42p which randomly explore the cell periphery. Our integrated computational and in vivo analyses of these waves reveal a negative feedback loop that competes with the aforementioned positive feedback loops to regulate Cdc42p activity and confer dynamic responsiveness on the robust initiation of cell polarization.

Drosophila Hemopoiesis and Cellular Immunity

“…When Cdc42 signaling was blocked in embryonic plasmatocytes, they were still able to migrate to the wound, but the motility of the plasmatocytes was affected. Similar to what has been described for both yeast and mammalian cells, hemocytes lacking Cdc42 were not able to maintain their cell polarity (43,48). These results show that, similar to mammalian leukocytes, Drosophila plasmatocytes require the Rho family GTPases for proper migration to wound sites.…”

Identification of Novel Membrane-binding Domains in Multiple Yeast Cdc42 Effectors

“…In this regard it is noteworthy that Gic2 "CRIB" fragments used as reporters for active Cdc42 during yeast cell polarization (Ozbudak et al, 2005) include both the CRIB domain and the BR domain identified here.…”

“…18, December 2007protein-protein interaction affinity to be weak, which may permit more dynamic sampling of the status of the protein partner (Fivaz and Meyer, 2003). Indeed, even during the slow protrusive growth of yeast cells, polarized Cdc42 targets can be extremely dynamic (Ozbudak et al, 2005).…”

Rho GTPase activity zones and transient contractile arrays

“…Self-amplification has been described for Cdc42 activation during yeast bud site selection and may involve both direct modulation of Cdc42 by GEFs and GAPs or indirect modulation via actin-based transport. (28,29,42,61,62) Another plausible positive feedback mechanism can be proposed for the cytokinetic Rho zones. Accumulation of active Rho might activate PIP kinase, (63) thereby promoting the observed accumulation of active PIP2 in the furrow.…”