Collapsin response mediator protein (CRMP) family proteins are cytosolic phosphoproteins involved in semaphorin 3A-mediated neuronal cell growth cone collapse and cancer invasion. We identified a novel human isoform of CRMP family proteins named long form CRMP-1 (LCRMP-1), which was different from the known invasion suppressor, CRMP-1, in its molecular weight and the N-terminal exon-1. This study was aimed to elucidate the clinical significance of LCRMP-1 in non-small cell lung cancer (NSCLC) patients. Full-length human LCRMP-1 was cloned from lung adenocarcinoma based on the Expressed Sequence Tags (EST) database. We generated LCRMP-1 specific antibody and subsequent in vitro and in vivo invasion assays showed positive correlations between LCRMP-1 expression and lung cancer cell invasiveness. We further demonstrated that high LCRMP-1 mRNA expressions were associated with poor overall and disease-free survivals (P=0.004 and 0.006, respectively, log-rank test) in 72 NSCLC patients. The results were confirmed in an independent cohort of 54 NSCLC patients by immunohistochemistry (P=0.032, log-rank test). The metastatic lymph nodes showed higher LCRMP-1 expressions as compared with the paired primary lung tumors (P=0.012, McNemar's test). In conclusion, LCRMP-1 was a cancer invasion enhancer that could be a novel prognostic biomarker in NSCLC.
"The metastatic lymph nodes demonstrated higher LCRMP1 expression when compared with that of the primary lung tumors. Therefore, LCRMP1 was considered to be a cancer invasion enhancer, which may present as a novel prognostic biomarker in NSCLC (41). To further understand the mechanisms associated with the cancer cell migration and invasiveness of LCRMP1, Pan et al (40) also revealed that the overexpression of LCRMP1 in non-invasive human cell lines enhances filopodia formation and cancer cell migration and invasion via the stabilization of actin through binding to the Wishott-Aldrich syndrome protein family 1 (WAVE-1) protein. "
[Show abstract][Hide abstract] 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.
"The CRMP family is composed of five family members (CRMP1–5) in vertebrates , , , , . Each CRMP allele produces two transcripts that differ in their amino terminal domains producing a long (L-CRMP) and short (S-CRMP) isoforms that have been alternatively referred to as ‘a’ and ‘b’ isoforms , , , . The CRMPs have been implicated in regulating axon path finding and neurite outgrowth , , , , , , . "
[Show abstract][Hide abstract] ABSTRACT: Glycogen Synthase Kinase 3 (GSK3) has been implicated in regulating chromosomal alignment and mitotic progression but the physiological substrates mediating these GSK3-dependent effects have not been identified. Collapsin Response Mediator Protein 4 (CRMP4) is a cytosolic phosphoprotein known to regulate cytoskeletal dynamics and is a known physiological substrate of GSK3. In this study, we investigate the role of CRMP4 during mitosis.
Here we demonstrate that during mitosis CRMP4 phosphorylation is regulated in a GSK3-dependent manner. We show that CRMP4 localizes to spindle microtubules during mitosis and loss of CRMP4 disrupts chromosomal alignment and mitotic progression. The effect of CRMP4 on chromosomal alignment is dependent on phosphorylation by GSK3 identifying CRMP4 as a critical GSK3 substrate during mitotic progression. We also provide mechanistic data demonstrating that CRMP4 regulates spindle microtubules consistent with its known role in the regulation of the microtubule cytoskeleton.
Our findings identify CRMP4 as a key physiological substrate of GSK3 in regulating chromosomal alignment and mitotic progression through its effect on spindle microtubules.
PLoS ONE 12/2010; 5(12):e14345. DOI:10.1371/journal.pone.0014345 · 3.23 Impact Factor
"The CRMP family consists of five family members (CRMP1-5) in vertebrates (Goshima et al., 1995; Minturn et al., 1995; Byk et al., 1996; Gaetano et al., 1997; Inatome et al., 2000) that regulate aspects of axon pathfinding and neurite outgrowth (Hedgecock et al., 1985; Siddiqui and Culotti, 1991; Goshima et al., 1995; Minturn et al., 1995; Quinn et al., 1999, 2003; Yoshimura et al., 2005). Each CRMP allele produces two transcripts which differ in their N terminus, yielding long (L-CRMP) and short (S-CRMP) isoforms, which have alternatively been referred to as " a " and " b " isoforms (Quinn et al., 2003; Yuasa-Kawada et al., 2003; Alabed et al., 2007; Pan et al., 2010). "
[Show abstract][Hide abstract] ABSTRACT: Myelin-associated inhibitors (MAIs) contribute to failed regeneration in the CNS. The intracellular signaling pathways through which MAIs block axonal repair remain largely unknown. Here, we report that the kinase GSK3beta is directly phosphorylated and inactivated by MAIs, consequently regulating protein-protein interactions that are critical for myelin-dependent inhibition. Inhibition of GSK3beta mimics the neurite outgrowth inhibitory effect of myelin. The inhibitory effects of GSK3beta inhibitors and myelin are not additive indicating that GSK3beta is a major effector of MAIs. Consistent with this, overexpression of GSK3beta attenuates myelin inhibition. MAI-dependent phosphorylation and inactivation of GSK3beta regulate phosphorylation of CRMP4, a cytosolic regulator of myelin inhibition, and its ability to complex with RhoA. Introduction of a CRMP4 antagonist attenuates the neurite outgrowth inhibitory properties of GSK3beta inhibitors. We describe the first example of GSK3beta inactivation in response to inhibitory ligands and link the neurite outgrowth inhibitory effects of GSK3beta inhibition directly to CRMP4. These findings raise the possibility that GSK3beta inhibition will not effectively promote long-distance CNS regeneration following trauma such as spinal cord injury.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 04/2010; 30(16):5635-43. DOI:10.1523/JNEUROSCI.6154-09.2010 · 6.34 Impact Factor
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