Regulation of ErbB Receptors by the Ca Sensor Protein Calmodulin in Cancer

Overview

Journal Biomedicines

Specialty Biomedical Engineering

Date 2023 Mar 29

PMID 36979639

Authors

Antonio Villalobo

Affiliations

Soon will be listed here.

Abstract

Overexpression and mutations of the epidermal growth factor receptor (EGFR/ErbB1/HER1) and other tyrosine kinase receptors of the ErbB family (ErbB2/HER2, ErbB3/HER3 and ErbB4/HER4) play an essential role in enhancing the proliferation, the migratory capacity and invasiveness of many tumor cells, leading to cancer progression and increased malignancy. To understand these cellular processes in detail is essential to understand at a molecular level the signaling pathways and regulatory mechanisms controlling these receptors. In this regard, calmodulin (CaM) is a Ca-sensor protein that directly interacts with and regulates ErbB receptors, as well as some CaM-dependent kinases that also regulate these receptors, particularly EGFR and ErbB2, adding an additional layer of CaM-dependent regulation to this system. In this short review, an update of recent advances in this area is presented, covering the direct action of Ca/CaM on the four ErbB family members mostly in tumor cells and the indirect action of Ca/CaM on the receptors via CaM-regulated kinases. It is expected that further understanding of the CaM-dependent mechanisms regulating the ErbB receptors in future studies could identify new therapeutic targets in these systems that could help to control or delay cancer progression.

Citing Articles

The calcium sensor AtCML8 contributes to Arabidopsis plant cell growth by modulating the brassinosteroid signaling pathway.

Lucchin A, Fouassier H, Robe E, Mbengue M, Aguilar M, San Clemente H Plant J. 2024; 121(1):e17179.

PMID: 39621453 PMC: 11712026. DOI: 10.1111/tpj.17179.

Purinergic Ca Signaling as a Novel Mechanism of Drug Tolerance in BRAF-Mutant Melanoma.

Stauffer P, Brinkley J, Jacobson D, Quaranta V, Tyson D Cancers (Basel). 2024; 16(13).

PMID: 39001489 PMC: 11240618. DOI: 10.3390/cancers16132426.

Purinergic Ca signaling as a novel mechanism of drug tolerance in BRAF mutant melanoma.

Stauffer P, Brinkley J, Jacobson D, Quaranta V, Tyson D bioRxiv. 2023; .

PMID: 37961267 PMC: 10635130. DOI: 10.1101/2023.11.03.565532.

References

Holt S, Alexander P, Inman C, Davies D . Epidermal growth factor induced tyrosine phosphorylation of nuclear proteins associated with translocation of epidermal growth factor receptor into the nucleus. Biochem Pharmacol. 1994; 47(1):117-26. DOI: 10.1016/0006-2952(94)90444-8. View

Komuro A, Nagai M, Navin N, Sudol M . WW domain-containing protein YAP associates with ErbB-4 and acts as a co-transcriptional activator for the carboxyl-terminal fragment of ErbB-4 that translocates to the nucleus. J Biol Chem. 2003; 278(35):33334-41. DOI: 10.1074/jbc.M305597200. View

Panina S, Stephan A, la Cour J, Jacobsen K, Kallerup L, Bumbuleviciute R . Significance of calcium binding, tyrosine phosphorylation, and lysine trimethylation for the essential function of calmodulin in vertebrate cells analyzed in a novel gene replacement system. J Biol Chem. 2012; 287(22):18173-81. PMC: 3365693. DOI: 10.1074/jbc.M112.339382. View

Li H, Panina S, Kaur A, Ruano M, Sanchez-Gonzalez P, la Cour J . Regulation of the ligand-dependent activation of the epidermal growth factor receptor by calmodulin. J Biol Chem. 2011; 287(5):3273-81. PMC: 3270982. DOI: 10.1074/jbc.M111.317529. View

Liu Y, Liu Z, Wang K . The Ca-activated chloride channel ANO1/TMEM16A: An emerging therapeutic target for epithelium-originated diseases?. Acta Pharm Sin B. 2021; 11(6):1412-1433. PMC: 8245819. DOI: 10.1016/j.apsb.2020.12.003. View

Novak U, Walker F, Kaye A . Expression of EGFR-family proteins in the brain: role in development, health and disease. J Clin Neurosci. 2001; 8(2):106-11. DOI: 10.1054/jocn.2000.0799. View

Hynes N, MacDonald G . ErbB receptors and signaling pathways in cancer. Curr Opin Cell Biol. 2009; 21(2):177-84. DOI: 10.1016/j.ceb.2008.12.010. View

Feinmesser R, Wicks S, Taverner C, Chantry A . Ca2+/calmodulin-dependent kinase II phosphorylates the epidermal growth factor receptor on multiple sites in the cytoplasmic tail and serine 744 within the kinase domain to regulate signal generation. J Biol Chem. 1999; 274(23):16168-73. DOI: 10.1074/jbc.274.23.16168. View

Ni C, Murphy M, Golde T, Carpenter G . gamma -Secretase cleavage and nuclear localization of ErbB-4 receptor tyrosine kinase. Science. 2001; 294(5549):2179-81. DOI: 10.1126/science.1065412. View

10.

Hait W, Morris S, Lazo J, Figlin R, Durivage H, White K . Phase I trial of combined therapy with bleomycin and the calmodulin antagonist, trifluoperazine. Cancer Chemother Pharmacol. 1989; 23(6):358-62. DOI: 10.1007/BF00435836. View

11.

Countaway J, Nairn A, Davis R . Mechanism of desensitization of the epidermal growth factor receptor protein-tyrosine kinase. J Biol Chem. 1992; 267(2):1129-40. View

12.

Jura N, Endres N, Engel K, Deindl S, Das R, Lamers M . Mechanism for activation of the EGF receptor catalytic domain by the juxtamembrane segment. Cell. 2009; 137(7):1293-307. PMC: 2814540. DOI: 10.1016/j.cell.2009.04.025. View

13.

Holt S, Alexander P, Inman C, Davies D . Ligand-induced translocation of epidermal growth factor receptor to the nucleus of NR6/HER fibroblasts is serum dependent. Exp Cell Res. 1995; 217(2):554-8. DOI: 10.1006/excr.1995.1122. View

14.

Villalobo A . The multifunctional role of phospho-calmodulin in pathophysiological processes. Biochem J. 2018; 475(24):4011-4023. PMC: 6305829. DOI: 10.1042/BCJ20180755. View

15.

Deb T, Coticchia C, Barndt R, Zuo H, Dickson R, Johnson M . Pregnancy-upregulated nonubiquitous calmodulin kinase induces ligand-independent EGFR degradation. Am J Physiol Cell Physiol. 2008; 295(2):C365-77. PMC: 2518423. DOI: 10.1152/ajpcell.00449.2007. View

16.

Dittmann K, Mayer C, Fehrenbacher B, Schaller M, Kehlbach R, Rodemann H . Nuclear EGFR shuttling induced by ionizing radiation is regulated by phosphorylation at residue Thr654. FEBS Lett. 2010; 584(18):3878-84. DOI: 10.1016/j.febslet.2010.08.005. View

17.

Hait W . Targeting calmodulin for the development of novel cancer chemotherapeutic agents. Anticancer Drug Des. 1987; 2(2):139-49. View

18.

Biscardi J, Maa M, Tice D, Cox M, Leu T, Parsons S . c-Src-mediated phosphorylation of the epidermal growth factor receptor on Tyr845 and Tyr1101 is associated with modulation of receptor function. J Biol Chem. 1999; 274(12):8335-43. DOI: 10.1074/jbc.274.12.8335. View

19.

Hynes N, Lane H . ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer. 2005; 5(5):341-54. DOI: 10.1038/nrc1609. View

20.

Theroux S, Nair N, Countaway J, Robinson H, Davis R . Increased oncogenic potential of ErbB is associated with the loss of a COOH-terminal domain serine phosphorylation site. J Biol Chem. 1992; 267(12):7967-70. View