Collapsin Response Mediator Proteins: Their Biological Functions and Pathophysiology in Neuronal Development and Regeneration

Abstract

Collapsin response mediator proteins (CRMPs), which consist of five homologous cytosolic proteins, are one of the major phosphoproteins in the developing nervous system. The prominent feature of the CRMP family proteins is a new class of microtubuleassociated proteins that play important roles in the whole process of developing the nervous system, such as axon guidance, synapse maturation, cell migration, and even in adult brain function. The CRMP C-terminal region is subjected to posttranslational modifications such as phosphorylation, which, in turn, regulates the interaction between the CRMPs and various kinds of proteins including receptors, ion channels, cytoskeletal proteins, and motor proteins. The gene-knockout of the CRMP family proteins produces different phenotypes, thereby showing distinct roles of all CRMP family proteins. Also, the phenotypic analysis of a non-phosphorylated form of CRMP2-knockin mouse model, and studies of pharmacological responses to CRMP-related drugs suggest that the phosphorylation/dephosphorylation process plays a pivotal role in pathophysiology in neuronal development, regeneration, and neurodegenerative disorders, thus showing CRMPs as promising target molecules for therapeutic intervention.

Proteomic Analysis Unveils Expressional Changes in Cytoskeleton- and Synaptic Plasticity-Associated Proteins in Rat Brain Six Months after Withdrawal from Morphine

“…Whereas the N-terminal dihydropyrimidinase-like domain appears to promote microtubule assembly, the C-terminal region of Crmp1 and Crmp2 (Dpysl2) is sufficient to stabilize the microtubules [ 76 ]. The phosphorylation of Crmps at its C-terminal domains causes microtubule destabilization, while inhibition of the C-terminal phosphorylation has a stabilizing effect [ 98 ]. The residues Thr509, Thr514 and Ser518 at the C-terminus of collapsin response mediator proteins are phosphorylated by GSK-3β [ 76 ].…”

Phosphorylation of Collapsin Response Mediator Protein 1 (CRMP1) at Tyrosine 504 residue regulates Semaphorin 3A‐induced cortical dendritic growth

“…We found that the Tyr504 of CRMP1 is the phosphorylation site of Fyn, confirming previous report (Buel et al., 2010). The C‐terminal region of CRMPs is attributed by post‐translational modification including phosphorylation and oxidation and alters the function of CRMPs (Morinaka et al., 2011; Nakamura et al., 2020; Yoshimura et al., 2005). For example, while non‐phosphorylated CRMP2 participates in tubulin‐dimer transport, phosphorylation of CRMP2 at Ser522 by Cdk5 switches its role in Sema3A signaling (Schmidt & Strittmatter, 2007).…”

“…CRMPs comprise five members (CRMP1‐5) (Nakamura et al., 2020; Schmidt & Strittmatter, 2007). CRMP1 and CRMP2 have been shown to be involved in Sema3A signaling in vitro and in vivo.…”

Cannabinoid Receptor 1 associates to different molecular complexes during GABAergic neuron maturation

“…Other protein associated with CB 1 is USHBP1, related to the Usher syndrome that presents retinal damage and defective neuronal development (Hass et al., 2013). Also, proteins involved in cytoskeleton modulation and neuronal morphology and maturation may be worth to consider, like Dihydropyrimidinase Like 2 (DPYSL2), a mediator of growth cone collapse, that may modify axon number, length, and neuronal polarity (Nakamura et al 2020), the Myosin phosphatase Rho‐interacting protein (MPRIP), required for the regulation of the actin cytoskeleton by RhoA and ROCK1 (Mulder et al., 2003; Surks et al., 2003), the Ephrin type‐A receptor 8 (EPHA8), in which downstream effectors is included FYN which promotes cell adhesion upon activation by EPHA8 and the MAP kinases in the stimulation of neurite outgrowth (Gu et al., 2005) or Tenascin‐R (TNR), a neural extracellular matrix (ECM) protein involved in interactions that can evoke a stable adhesion and differentiation or repulsion and inhibition of neurite growth (Roll & Faissner, 2019). Several works have described CB 1 involvement in axon growth, actin and tubulin cytoskeletal regulation and neuronal morphology, and these proteins might participate in those mechanisms (Berghuis et al., 2007; Harkany et al., 2007; Njoo et al., 2015; Roland et al., 2014).…”