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Review
, 600, 1-11

The CRMP Family of Proteins and Their Role in Sema3A Signaling

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Review

The CRMP Family of Proteins and Their Role in Sema3A Signaling

Eric F Schmidt et al. Adv Exp Med Biol.

Abstract

The CRMP proteins were originally identified as mediators of Sema3A signaling and neuronal differentiation. Much has been learned about the mechanism by which CRMPs regulate cellular responses to Sema3A. In this review, the evidence for CRMP as a component of the Sema3A signaling cascade and the modulation of CRMP by plexin and phosphorylation are considered. In addition, current knowledge of the function of CRMP in a variety of cellular processes, including regulation of the cytoskeleton and endocytosis, is discussed in relationship to the mechanisms of axonal growth cone Sema3A response. The secreted protein Sema3A (collapsin-1) was the first identified vertebrate semaphorin. Sema3A acts primarily as a repulsive axon guidance cue, and can cause a dramatic collapse of the growth cone lamellipodium. This process results from the redistribution of the F-actin cytoskeleton and endocytosis of the growth cone cell membrane. Neuropilin-1 (NP1) and members of the class A plexins (PlexA) form a Sema3A receptor complex, with NP1 serving as a high-affinity ligand binding partner, and PlexA transducing the signal into the cell via its large intracellular domain. Although the effect of Sema3A on growth cones was first described nearly 15 years ago, the intracellular signaling pathways that lead to the cellular effects have only recently begun to be understood. Monomeric G-proteins, various kinases, the redox protein, MICAL, and protein turnover have all been implicated in PlexA transduction. In addition, the collapsin-response-mediator protein (CRMP) family of cytosolic phosphoproteins plays a crucial role in Sema3A/NP1/PlexA signal transduction. Current knowledge regarding CRMP functions are reviewed here.

Figures

Figure 1
Figure 1
Schematic depicting the regulation of CRMP by Sema3A signaling. A) CRMP is a cytosolic phosphoprotein that exists as a heterotetramer and can bind to the kinase Fes. In the absence of Sema3A, NP1 blocks CRMP-PlexA interactions. B) Upon Sema3A stimulation, the CRMP tetramer is recruited to the cytoplasmic domain of PlexA, undergoes a conformational change (oval shape), and is phosphorylated by Cdk5, GSK3β, and Fes. These events lead to a change in the CRMP activation state subsequently mediating cellular responses to Sema3A.
Figure 2
Figure 2
Mapping regulatory residues onto the crystal structure of CRMP1. A) The crystal structure of a CRMP1 monomer (top) and tetramer (bottom). The surface residues contributing to tetramerization are highlighted in orange (interface 1) and blue (interface 2) on a GRASP diagram of the CRMP1 monomer (top left). A ribbon diagram depicting α-helices and β-strands are shown for the CRMP1 monomer (top right). In the tetramer structure individual monomers are colored in blue, pink, cyan, and yellow with oligomerization interfaces 1 and 2 indicated. B) Residues involved in the regulation of CRMP activity are mapped onto the CRMP1 structure. (B, top left) Ribbon diagram of CRMP1 monomer is reflected 180° from that in A, and the C-terminal 80 amino acids are represented by the oval. The N-terminal “activation loop” is highlighted in pink on the GRASP diagram (upper right). All of the phosphorylation sites of CRMP are located on the C-terminal 80 amino acids that are not included in the crystal structure. A color version of this figure is available online at www.Eurekah.com.
Figure 3
Figure 3
A model for CRMP-mediated cellular responses to Sema3A. 1) CRMP binds to the AP2 vesicle adaptor complex proteins intersectin (ITSN) and Numb to facilitate endocytosis of the growth cone membrane and PlexA/NP1 Sema3A receptor complex. 2) Phosphorylation of CRMP by GSK3β blocks the ability of CRMP to bind to tubulin dimers and subsequently prevents microtubule polymerization. 3) The Sra-1/WAVE complex, effectors of Rac1, regulate actin dynamics and are recruited to the growing axon by their interaction with CRMP. Sema3A may prevent the interaction of CRMP with the Sra-1/WAVE complex, thus attenuating recruitment and polymerization of actin in the growth cone. 4) CRMP interacts with the Rac1 GAP α2-chimaerin. The GAP activity may then lead to the inactivation of a pool of Rac1 mediating actin dynamics and an inhibition of the Sra-1/WAVE complex. Another pool of Rac1 is activated by PlexA and promotes endocytosis (top). 5) CRMP binds to the Plexin-interacting protein, MICAL, and may modulate its oxidoreductase enzymatic activity. A red “X” indicates interactions or processes that may be blocked by Sema3A signaling. Refer to text for details. A color version of this figure is available online at www.Eurekah.com.

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