The cysteine-rich regions of the regulatory domains of Raf and protein kinase C as retinoid receptors

Vitamin A and its biologically active derivatives, the retinoids, are recog nized as key regulators of vertebrate development, cell growth, and differe ntiation. Although nuclear receptors have held the attention since their di scovery a decade ago, we report: here on serine/threonine kinases as a new class of retinoid receptors. The conserved cysteine-rich domain of the NH2- terminal regulatory domains of cRaf-1, as well as several select domains of the mammalian protein kinase C (PKC) isoforms alpha, delta, zeta, and mu, the Drosophila and yeast PKCs, were found to bind retinol with nanomolar af finity. The biological significance was revealed in the alternate redox act ivation pathway of these kinases. Retinol served as a cofactor to augment t he activation of both cRaf and PKC alpha by reactive oxygen, whereas the cl assical receptor-mediated pathway was unaffected by the presence or absence of retinol. We propose that bound retinol, owing to its electron transfer capacity, functions as a tag to enable the efficient and directed redox act ivation of the cRaf and PKC families of kinases.