Abstract
Collapsin response mediator protein 2 (CRMP2) is an adaptor protein that adds tubulin dimers to the growing tip of a microtubule. First described in neurons, it is now considered a ubiquitous protein that intervenes in processes such as cytoskeletal remodeling, synaptic connection and trafficking of voltage channels. Mounting evidence supports that CRMP2 plays an essential role in neuropathology and, more recently, in cancer. We have previously described a positive correlation between nuclear phosphorylation of CRMP2 and poor prognosis in lung adenocarcinoma patients. In this work, we studied whether this cytoskeleton molding protein is involved in cancer cell migration. To this aim, we evaluated CRMP2 phosphorylation and localization in the extending lamella of lung adenocarcinoma migrating cells using in vitro assays and in vivo confocal microscopy. We demonstrated that constitutive phosphorylation of CRMP2 impaired lamella formation, cell adhesion and oriented migration. In search of a mechanistic explanation of this phenomenon, we discovered that CRMP2 Ser522 phospho-mimetic mutants display unstable tubulin polymers, unable to bind EB1 plus-Tip protein and the cortical actin adaptor IQGAP1. In addition, integrin recycling is defective and invasive structures are less evident in these mutants. Significantly, mouse xenograft tumors of NSCLC expressing CRMP2 phosphorylation mimetic mutants grew significantly less than wild-type tumors. Given the recent development of small molecule inhibitors of CRMP2 phosphorylation to treat neurodegenerative diseases, our results open the door for their use in cancer treatment.
Highlights
Lung cancer is the most common malignant tumor and the leading cause of cancerrelated death worldwide; non-small cell lung cancer (NSCLC) is the most prevalent subtype.In 2020, there were 2.2 million tracheal, bronchial, and lung cancer cases globally, with1.8 million deaths, accounting for approximately 17% of all cancer-related deaths [1]
We provide preliminary in vivo evidence on the importance of correct Collapsin response mediator protein 2 (CRMP2) phosphorylation for tumor growth in a mouse model of lung adenocarcinoma
CRMP2 Expression Is Needed for Oriented Cell Migration
Summary
1.8 million deaths, accounting for approximately 17% of all cancer-related deaths [1] This high mortality rate and low 5-year survival are mainly due to the early onset of metastases, which often happens even before the detection of the primary tumor [2]. For this reason, the study of the migratory and invasive capacity of NSCLC cancer cells and the mechanisms involved in this process, constitutes a matter of continuous research to provide new ways to improve patient prognosis. Microtubules form highly dynamic scaffolds that give rise to and modify cellular protrusions [3]
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