PDCD10 Interacts with Ste20-related Kinase MST4 to Promote Cell Growth and Transformation via Modulation of the ERK Pathway

Abstract

PDCD10 (programmed cell death 10, TFAR15), a novel protein associated with cell apoptosis has been recently implicated in mutations associated with Cerebral Cavernous Malformations (CCM). Yeast two-hybrid screening revealed that PDCD10 interacts with MST4, a member of Ste20-related kinases. This interaction was confirmed by coimmunoprecipitation and colocalization assays in mammalian cells. Furthermore, the co-overexpression of PDCD10 and MST4 promoted cell proliferation and transformation via modulation of the extracellular signal-regulated kinase (ERK) pathway. Potent short interfering RNAs (siRNAs) against PDCD10 (siPDCD10) and MST4 (siMST4) were designed to specifically inhibit the expression of PDCD10 and MST4 mRNA, respectively. The induction of siPDCD10 or siMST4 resulted in decreased expression of endogenous PDCD10 or MST4, which was accompanied by reduced ERK activity and attenuated cell growth and anchorage-independent growth. On the other hand, siMST4 had similar effects in PDCD10-overexpressed cells. And more importantly, we confirmed that either overexpressing or endogenous PDCD10 can increase the MST4 kinase activity in vitro. Our results demonstrated that PDCD10 modulation of ERK signaling was mediated by MST4, and PDCD10 could be a regulatory adaptor necessary for MST4 function, suggesting a link between cerebral cavernous malformation pathogenesis and the ERK-MAPK cascade via PDCD10/MST4.

Germinal center kinases in immune regulation

“…PDCD10 can bind to and stabilize GCK-III kinases, as well as promoting their kinase activities. 78 The N-terminal homodimerization domain of PDCD10 can form a stable heterodimer with the C-terminal homodimerization domain of GCK-III, indicating that GCK-III and PDCD10 may function together as a complex.…”

“…PDCD10, a regulator of cell growth and migration, has been implicated in normal cardiovascular development as well as certain human pathologies. 54,77,78 The N-terminal domain of PDCD10 mediates homodimerization while the C-terminal domain structurally resembles the focal adhesion targeting (FAT) domain of focal adhesion kinase (FAK). 79 Constitutive expression of PDCD10 in peripheral blood T-cells has been correlated with cutaneous T-cell lymphoma.…”

“…78,81 We therefore hypothesize that the Golgi matrix protein GM130 might recruit MST4 depending on the phosphorylation and activation status of MST4. It is worth noting that the STRIPAK complex may also interact with GCK-II kinases MST1/2 and GCK-IV kinase misshapen/NIK-related kinase.…”

Structure-Function Analysis of Core STRIPAK Proteins

“…8) and was identified previously as an interactor for the GCKIII proteins (9,10). CCMs are vascular lesions of the brain characterized by enlarged capillaries that lack structural integrity and that form caverns that tend to bleed, leading to symptoms ranging from headaches and dizziness to severe strokes and death (reviewed in Ref.…”

CCM1 and the second life of proteins in adhesion complexes

“…Alternatively, serine threonine kinase (STK) 24, STK25, and mammalian sterile 2like 4 (MST4), were identified as interaction partners of CCM3 in a yeast-two-hybrid screen. 39,[105][106][107] Combined with the connection of MST4 with LKB1 function in cell polarity, 108 this indicates a potential role for CCM3 in cell polarity.…”