Wolfenson, H. | bioRxiv Science

bioRxiv2018

Tumor suppressor DAPK1 catalyzes adhesion assembly on rigid but anoikis on soft matrices

Cancer cells will normally grow on soft surfaces, but if rigidity sensing modules are restored in cancer cells, they will undergo apoptosis on soft surfaces (anoikis) like most normal cells. DAPK1 is a major tumor suppressor that activates cell death, but it is unclear how DAPK1 could activate anoikis through rigidity sensing. Here we find that when rigidity sensing is decreased through inhibition of DAPK1 activity, cells are transformed for growth on soft matrices. Further, DAPK1 catalyzes matrix adhesion assembly and is part of adhesions on rigid surfaces. Additional factors include DAPK1 phosphorylation of tropomyosin2.1, talin1 head domain and tyrosine phosphorylation of DAPK1 by Src. On soft surfaces, DAPK1 rapidly dissociates from the adhesion complexes and activates apoptosis that requires PTPN12 activity and talin1 head. Thus, DAPK1 is important for adhesion assembly on rigid surfaces and the activation of anoikis on soft surfaces through its binding to rigidity-sensing modules.

cell biology↗

bioRxiv2017

Stopping Transformed Growth with Cytoskeletal Proteins: Turning a Devil into an Angel

The major hallmark of cancer cells is uncontrollable growth on soft matrices (transformed growth), which indicates that they have lost the ability to properly sense the rigidity of their surroundings. Recent studies of fibroblasts show that local contractions by cytoskeletal rigidity sensor units block growth on soft surfaces and their depletion causes transformed growth. The contractile system involves many cytoskeletal proteins that must be correctly assembled for proper rigidity sensing. We tested the hypothesis that cancer cells lack rigidity sensing due to their inability to assemble contractile units because of altered cytoskeletal protein levels. In four widely different cancers, there were over ten-fold fewer rigidity-sensing contractions compared with normal fibroblasts. Restoring normal levels of cytoskeletal proteins restored rigidity sensing and rigidity-dependent growth in transformed cells. Most commonly, this involved restoring balanced levels of the tropomyosins 2.1 (often depleted by miR-21) and 3 (often overexpressed). Restored cells could be transformed again by depleting other cytoskeletal proteins including myosin IIA. Thus, the depletion of rigidity sensing modules enables growth on soft surfaces and many different perturbations of cytoskeletal proteins can disrupt rigidity sensing thereby causing transformed growth of cancer cells.

cell biology↗