The Hedgehog Pathway Effector Smoothened Exhibits Signaling Competency in the Absence of Ciliary Accumulation

Fan, Chih Wei; Chen, Baozhi; Franco, Irene; Lü, Jianming; Shi, Heping; Wei, Shuguang; Wang, Chang-Guang; Wu, Xiaofeng; Tang, Wei; Roth, Michael G.; Williams, Noelle S.; Hirsch, Emilio; Chen, Chuo; Lum, Lawrence

doi:10.1016/j.chembiol.2015.04.001

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“…3 Class II a PI3K (PI3K-C2a), 1 of the 3 members of the class II PI3K subfamily, has become the focus of recent studies, but its exact physiological role still remains enigmatic. [3][4][5][6][7][8] In vitro studies have implicated PI3K-C2a in intracellular membrane trafficking, endocytosis, exocytosis, and autophagy. [3][4][5] Recently, loss of the Pik3c2a gene in mouse was shown to cause early embryonic lethality (between embryonic day 10.5 and embryonic day 11.5) as a result of severe defects in angiogenesis and vascular barrier function, together with primary cilium organization.…”

Section: Introductionmentioning

confidence: 99%

“…[3][4][5] Recently, loss of the Pik3c2a gene in mouse was shown to cause early embryonic lethality (between embryonic day 10.5 and embryonic day 11.5) as a result of severe defects in angiogenesis and vascular barrier function, together with primary cilium organization. [6][7][8] More than 15 years ago, the group of Susan Rittenhouse suggested that a class II PI3K could be implicated in blood platelet activation, 9 but to our knowledge, no work has followed since then. Platelets are small, anucleated blood cells that play a vital role in hemostasis and thrombosis.…”

Section: Introductionmentioning

confidence: 99%

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Essential role of class II PI3K-C2α in platelet membrane morphology

Valet

Chicanne

Severac

et al. 2015

Blood

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Key Points• PI3K-C2a controls platelet membrane structure and remodeling.• PI3K-C2a is a key regulator of a basal housekeeping PI3P pool in platelets.The physiologic roles of the class II phosphoinositide 3-kinases (PI3Ks) and their contributions to phosphatidylinositol 3-monophosphate (PI3P) and PI(3,4)P 2 production remain elusive. Here we report that mice heterozygous for a constitutively kinase-dead PI3K-C2a display aberrant platelet morphology with an elevated number of barbell-shaped proplatelets, a recently discovered intermediate stage in the final process of platelet production. Platelets with heterozygous PI3K-C2a inactivation have critical defects in a-granules and membrane structure that are associated with modifications in megakaryocytes. These platelets are more rigid and unable to form filopodia after stimulation. Heterozygous PI3K-C2a inactivation in platelets led to a significant reduction in the basal pool of PI3P and a mislocalization of several membrane skeleton proteins known to control the interactions between the plasma membrane and cytoskeleton. These alterations had repercussions on the performance of platelet responses with delay in the time of arterial occlusion in an in vivo model of thrombosis and defect in thrombus formation in an ex vivo blood flow system. These data uncover a key role for PI3K-C2a activity in the generation of a basal housekeeping PI3P pool and in the control of membrane remodeling, critical for megakaryocytopoiesis and normal platelet production and function. (Blood. 2015;126(9):1128-1137

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