Mesenchymal Cell Invasion Requires Cooperative Regulation of Persistent Microtubule Growth by SLAIN2 and CLASP1

Abstract

Summary Microtubules regulate signaling, trafficking and cell mechanics but the respective contribution of these functions to cell morphogenesis and migration in 3D matrices is unclear. Here, we report that the microtubule plus-end tracking protein (+TIP) SLAIN2, which suppresses catastrophes, is not required for 2D cell migration but is essential for mesenchymal cell invasion in 3D culture and in a mouse cancer model. We show that SLAIN2 inactivation does not affect Rho GTPase activity, trafficking and focal adhesion formation. However, SLAIN2-dependent catastrophe inhibition determines microtubule resistance to compression and pseudopod elongation. Another +TIP, CLASP1, is also needed to form invasive pseudopods because it prevents catastrophes specifically at their tips. When microtubule growth persistence is reduced, inhibition of depolymerization is sufficient for pseudopod maintenance but not remodeling. We propose that catastrophe inhibition by SLAIN2 and CLASP1 supports mesenchymal cell shape in soft 3D matrices by enabling MTs to perform a load-bearing function.

Retinoic acid receptor‐α regulates synthetic events in human platelets

“…SLAIN2 is known to link microtubule plus end‐tracking proteins, binding to cytoplasmic linker proteins (CLIPs) and CLIP‐associated proteins, and controlling microtubule growth . Furthermore, it was demonstrated that invasive growth requires regulated microtubule growth by SLAIN and interaction partners . Future studies should ascertain how atRA signaling regulates SLAIN2 protein expression in platelets, and the function of this protein in health and disease.…”

Kinesin-4 KIF21B limits microtubule growth to allow rapid centrosome polarization in T cells

“…To establish a causal connection between MT overgrowth and defects in immune synapse formation, we sought for a way to mildly inhibit MT growth in KIF21B-KO cells. Our previous work has shown that a low dose of vinblastine mildly perturbs growth and promotes catastrophes but does not induce MT depolymerization (Bouchet et al, 2016;Mohan et al, 2013). Indeed, at a low (0.5 nM) vinblastine concentration, MT network was preserved and was similar to that in control cells but different from KIF21B-KO cells, as no circular MT bundles were present at the cell periphery (compare Figure S4B to Figure 2A).…”

The Mechanical Role of Microtubules in Tissue Remodeling

“…The last decade led to a sharp rise in evidence for microtubules as central structural components that counter compression, [ 30,46,62,64–69,77,105 ] thus contributing to the mechanical state of epithelial tissues. [ 77,78 ] Yet, to date our understanding of microtubule mechanics is strongly influenced by insights gained from in vitro models that do not reveal the complexity of mechanisms controlling the interplay between microtubules and their effectors (e.g., motor proteins, MAPs, modification enzymes).…”

“…Despite their favorable biophysical properties and their widespread deployment in a large variety of cellular contexts, our understanding of the mechanical contribution of microtubules to tissue formation is only now emerging. In the past years, several studies demonstrated their mechanical contribution to cell mechanics [ 46,62–69 ] and a tensegrity model was proposed, suggesting that the ability of microtubules to withstand compression balance tensional forces in vivo (reviewed in ref. [70]).…”