Project Details
Projekt
A dual STIM2 redox switch in melanoma immunology
Applicants
Professor Dr. Ivan Bogeski; Professor Dr. Markus Hoth
Subject Area
Biochemistry
Term
from 2014 to 2022
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 251900186
Ca2+ controls a wide variety of cellular functions. In many cell types, Ca2+ signals are generated by store-operated Ca2+ entry (SOCE) which is turned on following activation of plasma membrane receptors linked to the InsP3 signaling cascade. Following InsP3 generation, the endoplasmic reticulum (ER) is (partially) depleted of Ca2+ and the ER Ca2+ sensors STIM1 and STIM2 activate Orai1, 2, or 3 channels mediate Ca2+ entry through store-operated CRAC channels. We have shown that Orai1 and Orai2 are redox regulated via cysteine modifications, while Orai3 is redox insensitive. STIM1 has 5 cysteines whereas STIM2 has 10 additional cysteines whose functional role was elusive. Using redox proteomics, we have identified two of these STIM2 cysteines (C302 and C313) as thiol switches in STIM2 and found that H2O2 inhibits STIM2-mediated SOCE in a cysteine 302 and 313 dependent manner.Our recent studies revealed that STIM2-dependent Ca2+ entry regulates proliferation, tumor growth, migration and cell death in melanoma. We also showed that STIM2 is important for Ca2+ signals in primary human killer cells which require Ca2+ signals to mediate their cytotoxic functions and kill melanoma cells. Thus STIM2 may be considered as a thiol switch with a dual function, controlling both melanoma cells and killer cells within the tumor-immune (micro)environment.The hypothesis of this proposal therefore is that the thiol redox switch in STIM2 is an important determinant of melanoma biology and tumor-immune interaction. This will be tested with the following aims: 1) Determine the mechanism of oxidation-induced SOCE inhibition by STIM2 thiol switches, 2) Investigate the functional role of STIM2 thiol switches in melanoma, 3) Determine the functional role of the STIM2 thiol switches for killer cell Ca2+ signaling and their cytotoxicity against melanoma cells.
DFG Programme
Priority Programmes
