NHMRC ECF Fellowship (CJ Martin Biomedical): Investigating the cellular requirement for STIM1 phosphorylation and store-operated calcium entry suppression during mitosis: roles in development and canc (2014–2017)
Abstract:
The endoplasmic reticulum (ER) calcium sensor STIM1 is phosphorylated during mitosis and fails to rearrange to
near-plasma membrane puncta with ORAI1 following calcium store depletion. As a result, store-operated calcium entry (SOCE) is strongly suppressed during mitosis. The physiological reason for STIM1 phosphorylation and reduced SOCE during cell division is unclear; mutating candidate STIM1 phosphorylation sites does not markedly reduce the growth rate of cultured cells. However, cells grown on plastic in a
controlled culture environment would rarely encounter store-depleting stimuli during mitosis, and thus a role for STIM1 phosphorylation and SOCE suppression during mitosis may not be revealed until these experiments consider factors present in the cellular microenvironment.
I will investigate the consequences of overexpressing STIM1 with mutations to mitosis-specific phosphorylation sites on mammary gland development in a 3D culture model and using a transgenic mouse model. In addition, I will explore whether the requirement for STIM1
phosphorylation and reduced SOCE during mitosis can be exploited to disrupt aberrant cell division in cancer cells, which are exposed to a distinct tumour microenvironment. This work will provide valuable insights into the role of calcium signalling in development and cancer, and may reveal a novel strategy for targeting the vulnerability of cancer cells as they undergo cell division.
