3q21.1

AAT7,KRP,MLCK,MLCK1,MLCK108,MLCK210,MMIHS,MMIHS1,MSTP083,MYLK1,smMLCK

Cancers

Myosin light chain kinase (MLCK) plays a crucial role in the cell migration and tumor metastasis. Some somatic mutations in MYLK are associated with cancers (Greenman et al., 2007). MLCK is critical for adhesion turnover at the cell front, a process central to migration (Webb et al., 2004) and it is involved in membrane blebbing (Godin and Ferguson, 2010). Deficiency in MLC phosphorylation causes cytokinesis failure and multipolarity (hence genomic instability) in cancer cells (Wu et al., 2010).

Breast cancer

MLCK activity correlates the recruitment of nonmuscle myosin IIA and myosin IIB into the spreading margin of MDA-MB-231 breast cancer cells, with both myosin isoforms required for cell migration but only myosin IIB critical to lamellar protrusion (Betapudi et al., 2006). MLC phosphorylation by MLCK through β1-integrin is required for actin stress fiber formation and the dormancy-to-proliferation metastatic switch for latent breast cancer cells (Barkan et al., 2008; Barkan et al., 2011). MLCK functions downstream of Ras, MAP kinase kinase (MEK) and extracellular signal regulated kinase (ERK) to promote invasive migration of breast cancer cells in an integrin-selective manner, i.e., mediated by a β1-integrin (probably α5β1) and α5β5, but not by α5β3 (Mierke, 2011; Mierke et al., 2011b; Nguyen et al., 1999; Zhou et al., 2008). Endothelial nmMLCK is activated by invasive breast cancer cells at the invasion site, leading to regional MLC diphosphorylation and myosin contraction. Blocking endothelial MLC diphosphorylation blunts tumor transcellular (i.e., through individual endothelial cells), but not paracellular (i.e., through cell-cell junctions) invasion (Khuon et al., 2010). Human mammary tumor cells exhibit at least two modes of invasive migration, including the extracellular proteolysis-dependent mesenchymal mode (invadopodia-associated extracellular matrix degradation) (Alexander et al., 2008) and the proteolysis-independent amoeboid mode, with both modes mediated by MLCK and Rho kinase ROCK (Alexander et al., 2008; Torka et al., 2006). TNF induction of apoptosis and DNA fragmentation requires MLCK activation in mammary carcinoma and other cancer cell lines (Wright et al., 1993). MLCK is responsible for high proliferative ability of breast cancer cells via anti-apoptosis (Cui et al., 2010). The increase in MLC phosphorylation correlates with apoptotic blebbing (Mills et al., 1998). Subsequent MLC dephosphorylation that results from a proapoptotic agent or MLCK inhibition (inhibitor or antibody) precedes caspase activation (Fazal et al., 2005), which further induces apoptosis in vitro and in vivo, and retards the growth of mammary cancer cells in mice (Fazal et al., 2005; Gu et al., 2006).

Lung cancer

The invasiveness of tumor cells depends in part on their motility, which in turn depends on cytoskeletal function (Minamiya et al., 2005). The expression level of MLCK, the cytoskeletal regulator, correlates with disease recurrence and distant metastasis in non-small cell lung cancer (NSCLC) (Minamiya et al., 2005). E1AF, an Ets family transcription factor frequently overexpressed in NSCLCs, induces motility and invasion as well as tumorigenesis and metastasis in NSCLC cells in a MLCK-dependent pathway (Hakuma et al., 2005). A few anti-cancer drug candidates, including glabridin, 7-chloro-6-piperidin-1-yl-quinoline-5,8-dione (PT-262), and all-trans-retinoic acid (ATRA), inhibit cell metastasis by decreasing cancer cell migration and invasion of human lung adenocarcinoma A549 cells via modulation of expression (Gui et al., 2011) or activity (Tsai et al., 2011a; Tsai et al., 2011b) of MLCK. Glycosylphosphatidylinositol-anchored receptor CD24 is found to enhance invasion of A125 human lung cancer cells through increased generation or transmission of contractile forces which is dependent on MLCK activity (Mierke et al., 2011a).

Colon cancer

MLCK is differentially expressed in microsatellite stable (MSS) sporadic colon cancer and hereditary nonpolyposis colorectal cancer (HNPCC) (Lee et al., 2008). It is suggested to be a potential colon tumor marker. MLCK regulates transendothelial migration of colon cancer cells in E-selectin-mediated activation of p38 MAPK (Tremblay et al., 2006), and possibly via changing cellular contractility by regulation of adhesion sites and stress fibers (Krndija et al., 2010). Inhibition of MLCK suppresses peripheral accumulation of phospho-MLC and Src-induced formation of integrin-dependent adhesions in KM12C colon cancer cells, whereas at the same time restoring E-cadherin redistribution to regions of cell-cell contact (Avizienyte et al., 2004; Avizienyte et al., 2005; Nguyen et al., 2002).

Prostate cancer

Inhibitors of MLCK markedly reduce the invasiveness of prostate cancer cells due to impaired cellular motility (Tohtong et al., 2003). These inhibitors also retard the growth of established prostate tumor in vivo (Gu et al., 2006). MLCK is considered as a central mediator of migration, proliferation and invasion of prostatic adenocarcinoma cell line (Tohtong et al., 2003) downstream of PKC delta (Kharait et al., 2007), boric acid, and phenylboronic acid (McAuley et al., 2011) in DU145 cell line (metastatic prostate cancer cell line). The MYLK gene is one of the top seven most informative genes that discriminate between normal and tumoral prostate conditions by analyzing cDNA microarrays of approximately 25000 genes (Fujita et al., 2008). MLCK is down-regulated by androgens in human prostate cancer cells (Leveille et al., 2009).

Other cancers

MLC phosphorylation or MLCK activation is directly involved in the activation of membrane-associated actomyosin required for the collection of surface proteins into a cap structure in mouse T-lymphoma cells (analogous to muscle cell sliding filament contraction) (Bourguignon et al., 1981; Kerrick and Bourguignon., 1984). Inhibitors of MLCK (ML-7 and ML-9) induce differentiation of human monoblastic leukemia U937 cells (Makishima et al., 1991; Makishima et al., 1993; Yamamoto-Yamaguchi et al., 1996). Apoptotic membrane blebbing is accompanied by increased MLC phosphorylation and regulated by MLCK in PC12, a neuroendocrine tumor cell line (Mills et al, 1998). MLCK regulates the activation of volume-sensitive organic osmolyte/anion channels (VSOAC) by mediating hypotonicity-induced Ca²⁺ entry (not correlating with MLC phosphorylation) in cervical cancer cells (Shen et al., 2002).