Regulation of Cdc42 during cell migration

On March 11th, 2008, Dr. Xueliang Zhu’s laboratory (Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences) published a new article in Developmental Cell to reveal that Nudel, by binding Cdc42GAP, modulates Cdc42 activity at the leading edge of migrating cells. Their work reveals a new pathway in regulation of Cdc42, which helps to understand the regulation mechanism in cell migration significantly.

 

Cell movement on solid matrix is called cell migration. It is among the most basic functions of animal cells and plays essential roles in embryonic development, immune system, and tumor metastasis. Cdc42, a small GTPase, cycles between its active and inactive forms and functions as a molecular switch in regulating cell migration. This switch is turned on by its guanine nucleotide exchange factors (GEFs) and then turned off by its GTPase activating proteins (GAPs). Cdc42 is usually activated at the leading edge of migrating cells. This regional activation triggers a polarized organization of both actin and microtubule systems, dictating the direction of cell migration. Because migrating cells tend to change their direction from time to time, strict and dynamic regulation of Cdc42 activity is essential for directional cell migration. It is known that extracellular stimuli can regionally activate Cdc42 through GEFs. However, little is known how migrating cells regulate Cdc42 activity through GAPs.

 

Two graduate students in Dr. Zhu’s lab, Yidong Shen and Ning Li, discovered that Nudel is phosphorylated by protein kinase Erk upon stimuli of cell migration. Phosphorylated Nudel is in turn enriched to the leading edge of migrating cells, where it competes with Cdc42 for a GAP, Cdc42GAP. Consequently, Nudel stabilizes Cdc42 activity level. On the other hand, excessive active Cdc42 may control its activity by recruiting Cdc42GAP from Nudel. This mechanism contributes to elaborate and dynamic modulation of Cdc42 activity during cell migration.