title: Matrix rigidity differentially regulates invadopodia activity through ROCK1 and ROCK2.
abstract: ROCK activity increases due to ECM rigidity in the tumor microenvironment and promotes a malignant phenotype via actomyosin contractility. Invasive migration is facilitated by actin-rich adhesive protrusions known as invadopodia that degrade the ECM. Invadopodia activity is dependent on matrix rigidity and contractile forces suggesting that mechanical factors may regulate these subcellular structures through ROCK-dependent actomyosin contractility. However, emerging evidence indicates that the ROCK1 and ROCK2 isoforms perform different functions in cells suggesting that alternative mechanisms may potentially regulate rigidity-dependent invadopodia activity. In this study, we found that matrix rigidity drives ROCK signaling in cancer cells but that ROCK1 and ROCK2 differentially regulate invadopodia activity through separate signaling pathways via contractile (NM II) and non-contractile (LIMK) mechanisms. These data suggest that the mechanical rigidity of the tumor microenvironment may drive ROCK signaling through distinct pathways to enhance the invasive migration required for cancer progression and metastasis.
authors.affiliation: Department of Otolaryngology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Rachel J
authors.initials: RJ
authors.lastname: Jerrell
authors.affiliation: Department of Otolaryngology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA. Electronic address: aron.parekh@vanderbilt.edu.
authors.forename: Aron
authors.initials: A
authors.lastname: Parekh
mesh_terms: D001696:Biomechanical Phenomena; D045744:Cell Line, Tumor; D002465:Cell Movement; D005109:Extracellular Matrix / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D054461:Lim Kinases / Q000378:metabolism; D024462:Myosin Type II / Q000378:metabolism; D009361:Neoplasm Invasiveness; D010766:Phosphorylation; D011554:Pseudopodia / Q000378:metabolism*; D015398:Signal Transduction; D054460:rho-Associated Kinases / Q000378:metabolism*
chemical_list: D007527:Isoenzymes; D054461:Lim Kinases; C515851:ROCK1 protein, human; C515852:ROCK2 protein, human; D054460:rho-Associated Kinases; D024462:Myosin Type II
keywords: Cancer; Contractility; Invadopodia; Invasion; ROCK; Rigidity
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