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PRKD3
PRKD3 Full Name
protein kinase D3
PRKD3 Introduction
PRKD3, located on chromosome 2p23, encodes protein kinase D3, the third member of the PRKD serine/threonine kinase family alongside PRKD1 and PRKD2. PRKD3 shares the conserved architecture of two N-terminal DAG-binding C1 domains and a pleckstrin homology domain, but lacks the C-terminal PDZ-binding motif present in PRKD1/2 and contains a distinct alanine- and proline-rich N-terminal region. Unlike the primarily cytoplasmic PRKD1, PRKD3 localizes constitutively to both cytoplasm and nucleus, and its catalytic activity drives nuclear import. PRKD3 is activated by phorbol esters, G-protein-coupled receptor agonists, and downstream of novel PKC isoforms.
Figure 1.PRKD3 is involved in the regulation of various signaling pathways. (Source: Liu Y, et al. 2021)
Mechanistically, PRKD3 functions as a pleiotropic regulator of cell growth, survival, migration, invasion, angiogenesis, and vesicle trafficking. In breast cancer it stabilizes clusterin (CLU) by inhibiting its lysosomal degradation, sustaining oncogenic CLU-driven signaling and tumor growth. It also activates the ERK1/c-MYC axis, driving cell proliferation both in vitro and in vivo. In prostate cancer, PRKD3 depends on HSP90 for stability and promotes cell migration, while in triple-negative breast cancer it participates in maintaining the cancer stem cell pool via GEF-H1 signaling. Additional targets include HDAC5/7 and regulators of epithelial barrier function.
Clinically, PRKD3 is consistently overexpressed in aggressive tumor subtypes, particularly triple-negative breast cancer, where elevated protein levels correlate with poorer prognosis. Higher PRKD3 expression in hepatocellular carcinoma also predicts adverse outcomes, and the kinase promotes malignant progression in oral squamous cell carcinoma by downregulating KLF16. Paradoxically, PRKD3 deletion in mice exacerbates liver fibrosis, indicating context-dependent functions in normal tissue homeostasis. Pharmacological inhibitors such as CRT0066101, which target PRKD family members, have demonstrated preclinical efficacy in suppressing triple-negative breast cancer tumor growth, highlighting PRKD3 as a promising therapeutic target in oncology.
Alternate Names for PRKD3
PRKD3; protein kinase D3; EPK2; PKD3; PRKCN; PKC-NU; nPKC-NU; serine/threonine-protein kinase D3; protein kinase EPK2; protein kinase C, nu; protein kinase C nu type; protein-serine/threonine kinase;
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