| PRKD2, protein kinase D2, belongs to the protein kinase D family of serine/threonine kinases, a subfamily positioned downstream of protein kinase C, and its regulatory domain contains two cysteine-rich, zinc-finger-like C1a/C1b domains that mediate diacylglycerol and phorbol ester binding, followed by a pleckstrin homology domain that functions as a negative regulator of catalytic activity, giving PKD2 the structural means to convert transient DAG signals generated at the membrane into sustained downstream signaling rather than a brief pulse. Within this regulatory domain, the C1b subdomain specifically is required for phorbol ester binding and for gastrin-stimulated PKD2 activation, while a nuclear localization sequence embedded in the linker between C1a and C1b, together with a nuclear export signal within C1a itself, governs PKD2's nucleocytoplasmic shuttling independently of the PH domain's role in catalytic control. This shuttling becomes physiologically relevant following activation of the CCKB/gastrin receptor, where casein kinase 1 delta and epsilon phosphorylate PKD2 at Ser244, a modification that drives PKD2 accumulation in the nucleus and directs its substrate targeting there; once nuclear, PKD2 phosphorylates HDAC7, triggering HDAC7 nuclear export and thereby relieving HDAC7-mediated transcriptional repression of the orphan nuclear receptor NR4A1/Nur77, directly coupling a gastrin-receptor-initiated phosphorylation cascade to derepression of a specific downstream transcription factor. Independently of this transcriptional role, PKD2 functions as the predominant PKD isoform required for endothelial cell proliferation, migration, and in vitro angiogenesis: selective knockdown of PKD2, but not PKD1, in primary human endothelial cells markedly suppresses these angiogenic behaviors and, mechanistically, PKD2 is specifically required for expression of the growth factor receptors VEGFR2 and FGFR1, positioning PKD2 as a receptor-expression-controlling checkpoint operating upstream of these two angiogenic receptor tyrosine kinases rather than acting solely as a downstream effector of their signaling. PKD2 additionally operates downstream of TCR engagement, where it is activated independently of ZAP70 and translocates to the nucleus to support IL2 promoter activity, and it separately participates in trans-Golgi network vesicle fission and polarized protein trafficking to the basolateral membrane, together with a role in secretory granule release. |
