By using a combination of optogenetic perturbation, FRET imaging, and phospho-proteomic analysis, we identified two key molecular players — CaMKII (Ca2+/calmodulin-dependent protein kinase II) and its phosphorylation target, Tumour Endothelial Marker 4 (TEM4) — that transduce the Ca2+ signal from TRPV4 to RhoA. The gene discussed is ARHGEF17; the disease is neoplasm.