CCM3 interacts with CCM2 indicating common pathogenesis for cerebral cavernous malformations

Abstract

Individuals carrying a mutation in one of the three cerebral cavernous malformation genes (CCM1/KRIT1, CCM2, CCM3) cannot be clinically distinguished, raising the possibility that they act within common molecular pathways. In this study, we demonstrate that CCM3 (PDCD10) coprecipitates and colocalizes with CCM2. We also show that CCM3 directly binds to serine/threonine kinase 25 (STK25, YSK1, SOK1) and the phosphatase domain of Fas-associated phosphatase-1 (FAP-1, PTPN13, PTP-Bas, PTP-BL). CCM3 is phosphorylated by STK25 but not by its other Yeast-Two hybrid interactor STK24, whereas the C-terminal catalytic domain of FAP-1 dephosphorylates CCM3. Finally, our experiments reveal that STK25 forms a protein complex with CCM2. Thus, our data link two proteins of unknown function, CCM3 and STK25, with CCM2, which is part of signaling pathways essential for vascular development and CCM pathogenesis.

CCM2 gene polymorphisms in Italian sporadic patients with cerebral cavernous malformation: A case-control study

“…Krit1 interacts with Rap-1A (Krev-1) (11), a member of the Ras superfamily of GTPases, with integrin cytoplasmic domain associated protein (ICAP1) α and CCM2 gene polymorphisms in Italian sporadic patients with cerebral cavernous malformation: A case-control study ROSALIA D'ANGELO 1 the phosphotyrosine binding (PTB) domain of malcavernin (10,12). The malcavernin protein may function as a scaffolding protein for MAP kinases (mitogen-activated protein kinase) that are essential in p38 activation responding to osmotic stress including MEKK (mitogen-activated protein kinase kinase kinase 3) and MKK3 (mitogen-activated protein kinase kinase); it also binds to Rac and actin (13,14).…”

“…It interacts directly with malcavernin independent of Krit1-malcavernin interaction (15). Malcavernin then links Krit1 and PDCD10 which alone would have little affinity with each other (13,16) and directly interacts with PDCD10 in the signalling pathways essential for vascular development and for CCM pathogenesis (13). Moreover, mutations in the PTB domain of malcavernin (amino acids 66-224), on conserved residues critical for NPXY⁄ F motif binding, are deleterious and can lead to inactivation of the protein.…”

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.…”

“…To date, it has been established that the three CCM proteins can form a complex. [39][40][41] How and whether disruption of this complex of CCM1, CCM2, and CCM3 is involved in the pathogenesis of CCM is still highly unknown.…”

Crystallization and preliminary crystallographic studies of CCM3 in complex with the C-terminal domain of MST4

“…Familial CCMs are linked to mutations in three CCM genes: ccm1-3 (Revencu & Vikkula, 2006). The proteins encoded by these three genes can interact with one another (Voss et al, 2007;Zawistowski et al, 2005), implying that they may share a common biochemical function.…”