Collapsin response mediator proteins: Potential diagnostic and prognostic biomarkers in cancers (Review)

Abstract

The collapsin response mediator proteins (CRMPs) were originally identified as mediators of semaphorin 3A signaling and neuronal differentiation. The CRMP family consists of five homologous cytosolic proteins, CRMP1-5. Altered expression levels of CRMPs have been observed in several malignant tumors, including lung, breast, colorectal, prostate, pancreatic and neuroendocrine lung cancer. The aim of the current study was to review the recent progress achieved in understanding the association between the different levels of CRMP expression in tumors and their involvement in pathological functions, such as tumor metastasis, disease progression, subtype differentiation and clinical outcome, to address the potential value of CRMPs as biomarkers for the diagnosis and prognosis of cancer patients.

Keywords: biomarker; collapsin response mediator proteins; metastasis; tumor suppressor.

Figure 1

Signaling pathways regulating growth cone collapse, axonal outgrowth and axonal branching through CRMP2. Sema3A triggers Rac1 activation, via its receptors NP-1 and PlexA1. This is followed by the activation of GSK-3β which subsequently phosphorylates CRMP2 at Ser-518, Thr-509 and Thr-514. The GSK-3β-mediated CRMP2 phosphorylation is dependent on the prior phosphorylation of CRMP2 at Ser-522 by Cdk-5. LPA induces CRMP2 phosphorylation at Thr-555 via RhoA and Rho, and BDNF, NT3, and Ras-GTP inhibit the activation of GSK-3β via PI3K and Akt to activate CRMP2. Neurofibromin directly interacts with or activates CRMP2 by inhibiting Cdk5, Rho or GSK-3β. Phosphorylated CRMP2 loses it affinity to tubulin heterodimers and subsequently induces growth cone collapse or axonal outgrowth inhibition. CRMP2, collapsin response mediator protein 2; Sema3A, semaphorin 3A; Rac1, Ras-related C3 botulinum toxin substrate 1; NP-1, neuropilin-1; PlexA1, plexin A1; GSK-3β, glycogen synthase kinase 3β; Cdk5, cyclin dependent kinase-5; LPA, lysophosphatidic acid; RhoA, Ras homolog family member A; BDNF, brain-derived neurotrophic factor; NT3, neurotrophin 3; PI3K, phopshoinositide 3-kinase; Akt, protein kinase B.