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 recognized as key regulators of vertebrate development, cell growth, and differentiation. Although nuclear receptors have held the attention since their discovery a decade ago, we report here on serine/threonine kinases as a new class of retinoid receptors. The conserved cysteine-rich domain of the NH(2)-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 affinity. The biological significance was revealed in the alternate redox activation pathway of these kinases. Retinol served as a cofactor to augment the activation of both cRaf and PKC alpha by reactive oxygen, whereas the classical 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 activation of the cRaf and PKC families of kinases.
Hoyos
B
B
Program in Immunology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Imam
A
A
Chua
R
R
Swenson
C
C
Tong
G X
GX
Levi
E
E
Noy
N
N
Hämmerling
U
U
D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D003545:Cysteine; D004330:Drosophila; D006801:Humans; D007527:Isoenzymes / Q000737:chemistry / Q000378:metabolism; D007700:Kinetics; D051379:Mice; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D011493:Protein Kinase C / Q000737:chemistry* / Q000378:metabolism*; D019908:Proto-Oncogene Proteins c-raf / Q000737:chemistry* / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000737:chemistry / Q000378:metabolism*; D012176:Retinoids / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000378:metabolism
D007527:Isoenzymes; D010446:Peptide Fragments; D018168:Receptors, Retinoic Acid; D012176:Retinoids; D019908:Proto-Oncogene Proteins c-raf; D011493:Protein Kinase C; D003545:Cysteine