Cellular and Developmental Biology of TRPM7 Channel-Kinase: Implicated Roles in Cancer
Abstract
:1. Introduction
2. Structure and Functions of TRPM7 Channel-Kinase
2.1. Structure of TRPM7
2.2. Biochemical and Electrophysiological Functions of TRPM7
2.3. Molecular Determinants of the Functions of TRPM7 Channel-Kinase
Mutations of Amino Acids | Effect on TRPM7 Function | Reference |
---|---|---|
Channel Pore Forming Segment (Human, aa. 1036–1056) | ||
m E1047Q (Glu→Gln) or h E1047A (Glu→Ala) | Loss of channel permeability to Mg2+ and Ca2+. | [50,53] |
m E1052Q (Glu→Gln) | Decreased Mg2+ and Ca2+ binding, and reduced Mg2+ and Ca2+ currents. | [50] |
h E1052A (Glu→Ala) | Decreased Mg2+ and Ca2+ binding, and reduced Mg2+ and Ca2+ currents. Partial reduction of proton conductivity. | [26,53] |
h D1054A (Asp→Ala) | Loss of proton conductivity. | [26] |
h D1059A (Asp→Ala) | Partial reduction of proton conductivity. | [26] |
Serine/Threonine Rich Region (Human, aa. 1380–1596) | ||
h T1482I (Thr→Ile) (a natural variant) (autophosphorylation site) | Increased sensitivity of channel to Mg2+-mediated suppression, and decreased current even at reduced [Mg2+]. | [51,54] |
m D1510 (Asp) | Caspase-mediated cleavage at Asp-1510 resulted in up-regulated channel activity. | [48] |
m S1511A (Ser→Ala) (autophosphorylation site) | No change in Ca2+ influx or sensitivity to Mg2+-mediated inhibition. | [38] |
m S1567A (Ser→Ala) (autophosphorylation site) | No change in Ca2+ influx or sensitivity to Mg2+-mediated inhibition. | [38] |
m Y1553F (Tyr→Phe) | ~75% of wild-type kinase activity. | [21] |
m Y1553L (Tyr→Leu) | ~50% of wild-type kinase activity. | |
m Y1553A (Tyr→Ala) | ~35% of wild-type kinase activity. | |
m R1558A (Arg→Ala) | ~15% of wild-type kinase activity. | [21] |
Kinase Domain (Human, aa. 1597–1824) | ||
m R1622L (Arg→Leu) (binding of PO43− of ATP) | <1% of wild-type kinase activity. | [38] |
h K1648R (Lys→Arg) or (phosphotransfer activity) | Diminished kinase activity. No change in channel activation in response to decreased free Mg2+ or Mg·ATP. Attenuated suppression of channel activity in response to free Mg2+ or Mg·ATP. | [11] |
m K1646R (Lys→Arg) (phosphotransfer activity) | <1% of wild-type kinase activity. | [38] |
m K1727A (Lys→Ala) | <1% of wild-type kinase activity. | [38] |
m N1731V (Asn→Val) (binding of PO43− of ATP) | <1% of wild-type kinase activity. | [38] |
m E1760A (Glu→Ala) | ~15% of wild-type kinase activity. | [21] |
m D1765N (Asp→Asn) or m D1765A (Asp→Ala) | <1% of wild-type kinase activity. | [38] |
m Q1767N (Gln→Asn) or m Q1767A (Gln→Ala) (metal binding) | <1% of wild-type kinase activity. | [38] |
m T1774S (Thr→Ser) | <1% of wild-type kinase activity. | [38] |
m T1774A (Thr→Ala) (binding of PO43− of ATP) | ~6% of wild-type kinase activity. | |
m D1775A (Asp→Ala) (metal binding) | <1% of wild-type kinase activity. | [38] |
m N1795A (Asn→Ala) (binding of peptide substrate) | ~2% of wild-type kinase activity. | [38] |
h G1799D (Gly→Asp) (phosphotransfer activity) | Diminished kinase activity. No change in channel activation in response to decreased free Mg2+ or Mg·ATP. Attenuated suppression of channel activity in response to free Mg2+ or Mg·ATP. | [11] |
3. TRPM7 Channel-Kinase in Normal Cellular Functions and Embryonic Development
3.1. TRPM7 in Cellular Processes and Physiological Functions
Cell Type | Functional Roles of TRPM7 Channel-Kinase | References |
---|---|---|
Lymphocytes | - Required for Mg2+-dependent viability and proliferation of chicken B lymphocytes (DT-40). - Required for proliferation involving phosphoinositide 3-kinase. - Required for differentiation. - Required for survival of T lymphocytes by preventing Fas-induced apoptosis. | [9,11,48,55] |
Neurons | - Oxidative stress activates TRPM7, which mediates anoxic death in human neurons; suppression of TRPM7 prevents anoxic neuronal death. - Facilitates fusion of cholinergic vesicle with plasma membrane and neurotransmitter release in cholinergic synaptic vesicles. | [23,56,57,58,59] |
Interstitial cells of Cajal | - Required for pacemaker activity of mouse duodenum. - Expressed in the interstitial cells of Cajal of human colon and small intestine and involved in the generation of the slow waves. | [60,61] |
Melanoblasts | - Required for survival of melanophores in zebrafish larvae. | [62,63] |
Vascular smooth muscle cells | - Functional TRPM7 channels translocate to plasma membrane in response to fluid flow. - Angiotensin II promotes proliferation of VSMCs in ascending aorta by increasing TRPM7 protein via Ca2+-influx-mediated activation of the Pyk2-ERK1/2-Elk-1 pathway. | [64,65] |
Osteoblasts | - Required for platelet-derived growth factor-induced proliferation and migration of human osteoblast MG-63 cells. | [66,67] |
Cervical epithelia | - Required for volume regulation as TRPM7-like currents activated by osmotic swelling-induced mechanical stretch of human cervical cancer HeLa cells. | [68] |
Mast cells | - Required for survival of human lung mast cells and human mast cell lines (LAD2, HMC-1). | [69] |
Fibroblasts | - Membrane tension activates TRPM7 channels and Ca2+ flickers, directing migration in human embryonic lung fibroblasts. - Transforming growth factor-β increased expression of TRPM7 in human atrial fibroblasts associated with myofibroblast differentiation and fibrogenesis in atrial fibrillation. | [24,70] |
Vascular endothelia | - Silencing TRPM7 promotes growth/proliferation and nitric oxide production viaERK in human umbilical vein vascular endothelial cells (HUVECs). - Silencing TRPM7 inhibits growth and migration of human microvascular endothelial cells (HMEC) but stimulates growth of HUVECs, partly because of impaired phosphorylation of ERK in HMEC. - Inhibition of TRPM7 leads to increased cell growth and migration in HUVECs. - TRPM7 contributes to hyperglycemia-induced injury of HUVECs. | [71,72,73] |
Bone marrow derived mesenchymal stem cells | - Required for survival of mouse bone marrow-derived mesenchymal stem cells; expression increased during osteogenesis suggesting its involvement in differentiation. | [74] |
Embryonic stem cells | - Kinase domain, but not kinase activity, is required for proliferation of mouse embryonic stem cells. | [29] |
Pancreatic epithelia | - Required for proliferation, cell cycle progression, and growth involving Mg2+ and Soc3a in exocrine pancreatic epithelia of zebrafish larvae. | [75] |
Hepatic stellate cells | - Required for survival by preventing TRAIL-induce apoptosis. - Regulates platelet-derived growth factor-BB-induced proliferation via PI3K and ERK in a rat hepatic stellate cell line (HSC-T6). - Required for activation and proliferation of HSCs by preventing endoplasmic reticulum stress-mediated apoptosis. | [76,77,78] |
Atrial myocytes | - TRPM7-like current was recorded in human atrial myocytes, and expression of TRPM7 is up-regulated in atria with atrial fibrillation or membrane rupture. | [79,80] |
Kidney cells | - TRPM7 contributes to elevated level of reactive oxygen species that leads to cell rounding mediated by the p38 MAPK/JNK-dependent activation of the Ca2+-dependent protease calpain in the immortalized human embryonic kidney cells (HEK 293), and during ischemia reperfusion in the mouse transplanted kidney. | [81,82,83] |
Adipocytes | - Required for proliferation and differentiation of 3T3-L1 pre-adipocytes. | [84] |
Prostate epithelia | - Increased Ca2+ to Mg2+ ratio in human prostate epithelia enhances. TRPM7-mediated currents and promotes cellular entry of Ca2+, leading to increase in cell proliferation. | [85] |
3.2. TRPM7 Channel-Kinase in Early Embryonic Development and Organogenesis
Developmental Processes | Mutant Phenotypes | Functional Roles | References |
---|---|---|---|
Embryogenesis | - Early embryonic lethality between E 6.5 and E7.5 in mouse. | - Required for intestinal absorption of Mg2+ and whole body magnesium homeostasis. | [29,86] |
Gastrulation | - Defects in cell polarization and alignment during convergent extension in Xenopus. | - TRPM7 channel but not the kinase domain required for regulating polarized cell movements during gastrulation involving Mg2+ via non-canonical Wnt signaling and modulation of the small GTPase Rac levels. | [87] |
Melanogenesis | - Skin hypopigmentation in zebrafish larvae. | - Required for survival of melanophores in zebrafish larvae. - Loss-of-function mutation in Trpm7 leads to cell death of melanophores that is dependent on melanin synthesis. | [62,63,75,88,89,90,91] |
Skeletogenesis | - Skeletal deformities in zebrafish with accelerated endochondral ossification and delayed intra-membranous ossification. - Dwarf zebrafish adults. | - Not reported. | [62] |
Thymopoiesis | - Selective deletion of Trpm7 in T-cell lineage accelerates thymic involution in mouse. | - Required for differentiation and maintenance of thymic epithelia. - Required for STAT3 activity in thymic medullary cells. | [86] |
Nervous system | - Defects in touch-response in zebrafish larvae. - Paralysis of hind legs of mouse with deletion of Trpm7 in committed neural crest progenitors; loss of large-diameter sensory neurons in lumbar dorsal root ganglion of mouse embryos depleted of TRPM7. | - Possibly required for synaptic release of neurotransmitters between sensory neurons and interneurons in zebrafish larvae. - Required for development of neural crest progenitors into dorsal root ganglion sensory neurons in mouse. - Required for differentiation or function of dopaminergic neurons in zebrafish larvae. | [59,92,93] |
Nephrogenesis | - Nephrolithiasis in zebrafish larvae. - Defect formation of kidney with relatively few glomeruli and large renal cysts in mouse. | - Required for homeostasis of whole body Mg2+ and Ca2+ in zebrafish involving stanniocalcin 1 and fibroblast growth factor 23. | [92,94] |
Exocrine pancreatic organogenesis | - Relatively small pancreas with immature acini and hypomorphic ducts in zebrafish larvae. | - Required for pancreatic epithelial proliferation and growth, which are sensitive to Mg2+ in extracellular medium and involving Socs3a. | [75,90,91] |
4. Expression and Roles of TRPM7 in Cancer
4.1. Oncologic Roles of TRPM7
Cancer | Expression | Functional roles of TRPM7 | References |
---|---|---|---|
Pancreatic adenocarcinoma | - Increased in human pancreatic adenocarcinoma tissues and cell lines. - Increased in chronic pancreatitis, pancreatic intra-epithelial neoplasms | - Required for cellular proliferation and cell cycle progression involving Mg2+. - Required for preventing replicative senescence. - Required for cell migration involving Mg2+. - Required for cell invasion. | [75,95,96,97,98] |
Breast carcinoma | - Over-expression in human breast carcinoma tissues and cell lines. - Increased expression in infiltrating ductal carcinoma with microcalcifications - Somatic mutation T720S (Thr→Ser) in a breast infiltrating ductal carcinoma | - Required for cancer cell proliferation in vitro. - Required for cancer cell migration in vitro and tumor metastasis in a mouse xenograft model. - Waixenicin A, TRPM7 blocker, inhibits growth and survival of breast cancer cells MCF-7. - TRPM7 involved in estrogen receptor-negative metastatic breast cancer cells migration through kinase domain. - Involved in ginsenoside Rd-induced apoptosis in cells. - Involved in epithelial mesenchymal transition. - TRPM7 mediates migration and invasion of breast cancer cells (MDA-MB-435) involving phosphorylation of Src and MAPK. | [99,100,101,102,103,104,105,106,107] |
Gastric carcinoma | - Expressed in human gastric adenocarcinoma cell lines (AGS, MKN-1, MKN-45, SNU-1, SNU-484) - Somatic mutation M830V (Met→Val) in gastric adenocarcinoma | - Required for cell survival involving Mg2+. - Waixenicin A, TRPM7 blocker, inhibits growth andsurvival of gastric cancer cells AGS. - Involved in ginsenoside Rd-induced apoptosis AGS cells. | [105,107,108,109,110] |
Head and neck Carcinoma | - Expressed in FaDu cells and SCC-25 cells. - High expression in 5-8F cells, low expression in 6-10B cells. | - Required for cell growth and proliferation. - Required for migration of nasopharyngeal carcinomacells (5-8F and 6-10B). - Proliferation of FaDu hypopharyngeal squamous cells (FaDu) inhibited by midazolam that targets TRPM7. | [111,112,113] |
Retinoblastoma | - Existence in 5-8F cells | - Required for cell proliferation. - Required for 5-8F cell migration. | [114] |
Melanoma | - Expressed in cell lines | - Not reported. | [63,115] |
Lung carcinoma | - Expressed in A549 cells | - Required for migration of A549 cells. | [116] |
Erythroleukemia | - TRPM7-like currents in cell lines. | - Not reported. | [117] |
Colon cancer | -TRPM7 (Thr1482Ile) polymorphism | - TRPM7 (Thr1482Ile) polymorphism associated with elevated risk of both adenomatous and hyperplastic polyps. - Individuals with TRPM7 (Thr1482Ile) polymorphism with a high Ca:Mg ratio intake in diet at a relatively high risk of developing adenoma and hyperplastic polyps. | [54] |
Leukemia | - Not reported. | - Waixenicin inhibits and T cell leukemia (Jurkat T lymphocytes) and rat basophilic leukemia cells (RBL1) through blocking TRPM7 channel activity. | [118] |
Neuroblastoma | - Not reported. | - In mouse neuroblastoma cells (N1E-115), TRPM7 promotes formation of Ca2+ sparking and invadosome by affecting actomyosin contractility independent from Ca2+ influx. | [119] |
Ovarian carcinoma | - Somatic mutation S406C (Ser→Cys) in ovarian serous carcinoma | - Not reported. | [107] |
Prostate cancer | - Expressed in human prostate cancer cell line DU145 | - Increased Ca2+ to Mg2+ ratio in prostate cancer cells enhances TRPM7-mediated currents and promotes cellular entry of Ca2+, leading to increase in cell proliferation. | [85] |
4.2. Potential Role of TRPM7 as a Cancer Biomarker and Therapeutic Target
5. Conclusion and Future Perspectives
Acknowledgments
Author Contributions
Conflicts of Interest
References
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Yee, N.S.; Kazi, A.A.; Yee, R.K. Cellular and Developmental Biology of TRPM7 Channel-Kinase: Implicated Roles in Cancer. Cells 2014, 3, 751-777. https://doi.org/10.3390/cells3030751
Yee NS, Kazi AA, Yee RK. Cellular and Developmental Biology of TRPM7 Channel-Kinase: Implicated Roles in Cancer. Cells. 2014; 3(3):751-777. https://doi.org/10.3390/cells3030751
Chicago/Turabian StyleYee, Nelson S., Abid A. Kazi, and Rosemary K. Yee. 2014. "Cellular and Developmental Biology of TRPM7 Channel-Kinase: Implicated Roles in Cancer" Cells 3, no. 3: 751-777. https://doi.org/10.3390/cells3030751