PAK4 Kinase Is Essential for Embryonic Viability and for Proper Neuronal Development

Qu, Jian; Li, Xiaofan; Novitch, Bennet G.; Zheng, Ye; Kohn, Matthew J.; Xie, Jianming; Kozinn, Spencer; Bronson, Roderick T.; Beg, Amer A.; Minden, Audrey

doi:10.1128/mcb.23.20.7122-7133.2003

Cited by 141 publications

(191 citation statements)

References 74 publications

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“…Brain lysates from Pak5/Pak6 double knockout mice revealed substantially decreased levels of phosphorylated Pacsin1 compared to the single knockouts (Fig. 5) with the residual phosphorylation likely due to the presence of Pak4, which is also expressed in the brain (13). Taken together, these data indicate that Pacsin1 is phosphorylated by Pak5 and Pak6 in vivo.…”

Section: Three Isoforms Ofsupporting

confidence: 65%

“…Among the group II Paks, only Pak4 is ubiquitously expressed and is essential for viability (13), whereas Pak5 and Pak6 have a more limited tissue expression pattern with especially high levels in the brain (14,15). Consistent with some level of functional redundancy between these Pak isoforms, no phenotype has been reported for PAK5 or PAK6 single knockout mice (10,16), but PAK5/PAK6 double knockout mice exhibit defects in behavior, memory, and learning (16).…”

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confidence: 69%

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Identification of neuronal substrates implicates Pak5 in synaptic vesicle trafficking

Strochlic

Concilio

Viaud

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Synaptic transmission is mediated by a complex set of molecular events that must be coordinated in time and space. While many proteins that function at the synapse have been identified, the signaling pathways regulating these molecules are poorly understood. Pak5 (p21-activated kinase 5) is a brain-specific isoform of the group II Pak kinases whose substrates and roles within the central nervous system are largely unknown. To gain insight into the physiological roles of Pak5, we engineered a Pak5 mutant to selectively radiolabel its substrates in murine brain extract. Using this approach, we identified two novel Pak5 substrates, Pacsin1 and Synaptojanin1, proteins that directly interact with one another to regulate synaptic vesicle endocytosis and recycling. Pacsin1 and Synaptojanin1 were phosphorylated by Pak5 and the other group II Paks in vitro, and Pak5 phosphorylation promoted Pacsin1-Synaptojanin1 binding both in vitro and in vivo. These results implicate Pak5 in Pacsin1-and Synaptojanin1-mediated synaptic vesicle trafficking and may partially account for the cognitive and behavioral deficits observed in group II Pak-deficient mice.

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Section: Three Isoforms Ofsupporting

confidence: 65%

mentioning

confidence: 69%

Identification of neuronal substrates implicates Pak5 in synaptic vesicle trafficking

Strochlic

Concilio

Viaud

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…The embryos have abnormalities in multiple organs, including the heart and brain. 75,76 Pak1 knockout mice are viable and appear normal. They do, however, have subtle abnormalities in the immune system.…”

Section: Developmental Functions Of Pak Kinases As Assessed By Studyimentioning

confidence: 99%

P21 activated kinases

Rane¹,

Minden²

2014

Small GTPases

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“…Pix and Pak participate in multiple cellular pathways and are downstream of the EGFR, integrins, and G coupled protein receptors (19,21,22). The in vivo roles of ␤Pix and Pak2 are unknown, but related Pix and Pak genes are critical for neural development in mice and humans (23)(24)(25).…”

mentioning

confidence: 99%

A βPix–Pak2a signaling pathway regulates cerebral vascular stability in zebrafish

Liu

Fraser

Faloon³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

103

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The vasculature tailors to the needs of different tissues and organs. Molecular, structural, and functional specializations are observed in different vascular beds, but few genetic models give insight into how these differences arise. We identify a unique cerebrovascular mutation in the zebrafish affecting the integrity of blood vessels supplying the brain. The zebrafish bubblehead (bbh) mutant exhibits hydrocephalus and severe cranial hemorrhage during early embryogenesis, whereas blood vessels in other regions of the embryo appear intact. Here we show that hemorrhages are associated with poor cerebral endothelial-mesenchymal contacts and an immature vascular pattern in the head. Positional cloning of bbh reveals a hypomorphic mutation in ␤Pix, a binding partner for the p21-activated kinase (Pak) and a guanine nucleotide exchange factor for Rac and Cdc42. ␤Pix is broadly expressed during embryonic development and is enriched in the brain and in large blood vessels. By knockdown of specific ␤Pix splice variants, we show that they play unique roles in embryonic vascular stabilization or hydrocephalus. Finally, we show that Pak2a signaling is downstream of ␤Pix. These data identify an essential in vivo role for ␤Pix and Pak2a during embryonic development and illuminate a previously unrecognized pathway specifically involved in cerebrovascular stabilization.angiogenesis ͉ hemorrhage ͉ hydrocephalus

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PAK4 Kinase Is Essential for Embryonic Viability and for Proper Neuronal Development

Cited by 141 publications

References 74 publications

Identification of neuronal substrates implicates Pak5 in synaptic vesicle trafficking

Identification of neuronal substrates implicates Pak5 in synaptic vesicle trafficking

P21 activated kinases

A βPix–Pak2a signaling pathway regulates cerebral vascular stability in zebrafish

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