Decoding how receptor tyrosine kinases (RTKs) mediate nuclear calcium signaling

Calcium (Ca²⁺) is a highly versatile intracellular messenger that regulates several cellular processes. Although it is unclear how a single-second messenger coordinates various effects within a cell, there is growing evidence that spatial patterns of Ca²⁺ signals play an essential role in determining their specificity. Ca²⁺ signaling patterns can differ in various cell regions, and Ca²⁺ signals in the nuclear and cytoplasmic compartments have been observed to occur independently. The initiation and function of Ca²⁺ signaling within the nucleus are not yet fully understood. Receptor tyrosine kinases (RTKs) induce Ca²⁺ signaling resulting from phosphatidylinositol 4,5-bisphosphate (PIP2) hydrolysis and inositol 1,4,5-trisphosphate (InsP3) formation within the nucleus. This signaling mechanism may be responsible for the effects of specific growth factors on cell proliferation and gene transcription. This review highlights the recent advances in RTK trafficking to the nucleus and explains how these receptors initiate nuclear calcium signaling.