TRPM7 regulates polarized cell movements

Department of Pharmacology, Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA.
Biochemical Journal (Impact Factor: 4.4). 03/2011; 434(3):513-21. DOI: 10.1042/BJ20101678
Source: PubMed


TRPM7 (transient receptor potential melastatin 7) is a Ca²+- and Mg²+-permeant ion channel in possession of its own kinase domain. As a kinase, the protein has been linked to the control of actomyosin contractility, whereas the channel has been found to regulate cell adhesion as well as cellular Mg²+ homoeostasis. In the present study we show that depletion of TRPM7 by RNA interference in fibroblasts alters cell morphology, the cytoskeleton, and the ability of cells to form lamellipodia and to execute polarized cell movements. A pulldown-purification assay revealed that knockdown of TRPM7 prevents cells from activating Rac and Cdc42 (cell division cycle 42) when stimulated to migrate into a cellular wound. Re-expression of TRPM7 reverses these phenotypic changes, as does, unexpectedly, expression of a kinase-inactive mutant of TRPM7. Surprisingly, expression of the Mg²+ transporter SLC41A2 (solute carrier family 41 member 2) is also effective in restoring the change in cell morphology, disruption of the cytoskeleton and directional cell motility caused by depletion of the channel-kinase. The results of the present study uncover an essential role for Mg²+ in the control of TRPM7 over the cytoskeleton and its ability to regulate polarized cell movements.

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    • "Since these Ca 2+ " sparks " guided directional migration in response to mechanical stimuli, the authors suggested that TRPM7 may have a role in the generation of traction forces at cell adhesions by decoding mechanical cues. Other studies have argued for a prominent role of TRPM7-mediated Mg 2+ influx in migration (Abed and Moreau, 2009; Callera et al., 2009; Rybarczyk et al., 2012; Su et al., 2011), possibly by regulating the activation of Rho-family GTPases (Liu et al., 2011; Su et al., 2011). Alternatively, permeation of either Ca 2+ or Mg 2+ by TRPM7 may activate the cytoskeletal regulator calpain through increases of ROS and nitric oxide that in turn activate p38 MAP kinase and c-Jun N-terminal kinase (Su et al., 2006, 2010). "
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    ABSTRACT: Transient Receptor Potential (TRP) cation channels represent a large and diverse family of ion channels that act as important transducers of sensory information. The Melastatin subfamily member TRPM7 has garnered much interest due to its functional kinase domain; a unique feature among ion channels. TRPM7 primarily conducts Ca2+ and Mg2+ and its activity is regulated by intracellular Mg2+, phospholipase C-mediated signaling and mechanical cues. A growing number of studies emphasize a regulatory role for TRPM7 in proliferation and cell survival as well as cytoskeletal reorganization during adhesion and migration. Knockout approaches in animal models have revealed that TRPM7 significantly contributes to embryonic development and organogenesis. In addition, a role for TRPM7 to the pathophysiology of several diseases has become evident in recent years. Here, we discuss how recent insights have contributed to our understanding of TRPM7 function and regulation in health and disease.
    Full-text · Article · Jul 2014 · European Journal of Cell Biology
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    • "Cell viability was quantified by manual cell counting and trypan blue exclusion. The recombinant adenoviruses expressing LacZ and GFP have been previously described (Su et al., 2011). The recombinant adenovirus expressing TRPM7-DN was engineered as follows. "
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    ABSTRACT: Transient receptor potential, melastatin-like 7 (Trpm7) is a combined ion channel and kinase implicated in the differentiation or function of many cell types. Early lethality in mice and frogs depleted of the corresponding gene impedes investigation of the functions of this protein particularly during later stages of development. By contrast, zebrafish trpm7 mutant larvae undergo early morphogenesis normally and thus do not have this limitation. The mutant larvae are characterized by multiple defects including melanocyte cell death, transient paralysis, and an ion imbalance that leads to the development of kidney stones. Here we report a requirement for Trpm7 in differentiation or function of dopaminergic neurons in vivo. First, trpm7 mutant larvae are hypomotile and fail to make a dopamine-dependent developmental transition in swim-bout length. Both of these deficits are partially rescued by the application of levodopa or dopamine. Second, histological analysis reveals that in trpm7 mutants a significant fraction of dopaminergic neurons lack expression of tyrosine hydroxylase, the rate-limiting enzyme in dopamine synthesis. Third, trpm7 mutants are unusually sensitive to the neurotoxin 1-methyl-4-phenylpyridinium, an oxidative stressor, and their motility is partially rescued by application of the iron chelator deferoxamine, an anti-oxidant. Finally, in SH-SY5Y cells, which model aspects of human dopaminergic neurons, forced expression of a channel-dead variant of TRPM7 causes cell death. In summary, a forward genetic screen in zebrafish has revealed that both melanocytes and dopaminergic neurons depend on the ion channel Trpm7. The mechanistic underpinning of this dependence requires further investigation.
    Full-text · Article · Nov 2013 · Developmental Biology
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    • "Key words: TRPM7, pancreatic cancer, cell migration, magnesium Additional Supporting Information may be found in the online version of this article. Grant sponsors: Ministère de la Recherche et de l'Enseignement Sup erieur, Conseil G en eral de Picardie, Ligue Contre le Cancer— Comit e de l'Aisne DOI: 10.1002/ijc.27487 History: Received 8 Aug 2011; Accepted 12 Jan 2012; Online 10 Feb 2012 Correspondence to:"
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    ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive forms of cancer with a tendency to invade surrounding healthy tissues, leading to a largely incurable disease. Despite many advances in modern medicine, there is still a lack of early biomarkers as well as efficient therapeutical strategies. The melastatin-related transient receptor potential 7 channel (TRPM7) is a nonselective cation channel that is involved in maintaining Ca(2+) and Mg(2+) homeostasis. It has been recently reported to regulate cell differentiation, proliferation and migration. However, the role of TRPM7 in PDAC progression is far to be understood. In our study, we show that TRPM7 is 13-fold overexpressed in cancer tissues compared to the healthy ones. Furthermore, TRPM7 staining is stronger in tumors with high grade, suggesting a correlation between TRPM7 expression and PDAC progression. Importantly, TRPM7 expression is inversely related to patient survival. In BxPC-3 cell line, dialyzing the cytoplasm during the patch-clamp whole-cell recording with a 0-Mg(2+) solution activated a nonselective current with a strong outward rectification. This cation current is inhibited by intracellular Mg(2+) and by TRPM7 silencing. The downregulation of TRPM7 by small interference RNA dramatically inhibited intracellular Mg(2+) fluorescence and cell migration without affecting cell proliferation, suggesting that TRPM7 contributes to Mg(2+) entry and cell migration. Moreover, external Mg(2+) following TRPM7 silencing fully restored the cell migration. In summary, our results indicate that TRPM7 is involved in the BxPC-3 cell migration via a Mg(2+)-dependent mechanism and may be a potential biomarker of poor prognosis of PDAC.
    Full-text · Article · Sep 2012 · International Journal of Cancer
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