Targeted disruption of the Pak5 and Pak6 genes in mice leads to deficits in learning and locomotion

Nekrasova, Tanya; Jobes, M.; Ting, Jenhao H.; Wagner, George C.; Minden, Audrey

doi:10.1016/j.ydbio.2008.07.006

Cited by 93 publications

(89 citation statements)

References 52 publications

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“…Pacsin1 binds to NR3A-containing NMDA receptors and promotes their endocytosis (39), and Synaptojanin1 has also been implicated in endocytosis (40), specifically in postsynaptic AMPA receptor downregulation (41). Pak5 −∕− ∕Pak6 −∕− mice exhibit defects in locomotion, learning, and memory (16), and based on our results, we propose that the cognitive and behavioral deficits observed in these mice may be partly attributable to altered endocytosis and vesicle trafficking. Learning and memory, in particular, are dependent on a form of synaptic plasticity known as long-term potentiation, a process that relies heavily on the density of neurotransmitter receptors within the postsynaptic membrane (42).…”

Section: Discussionsupporting

confidence: 55%

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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: Discussionsupporting

confidence: 55%

“…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). The molecular mechanisms underlying these cognitive defects, however, have yet to be determined.…”

mentioning

confidence: 93%

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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“…By focusing on dopaminergic regions (VTA and SN), we identified strong coexpression of Pak6 with Ar as well as Gr. Of interest, Pak6 is a known AR coregulator (31) and Pak6 KO mice show several locomotion and behavioral deficits that are likely related to disturbed dopaminergic transmission (32). Thus, this example of Pak6 coexpression underscores the feasibility of our methodology to find potential partners of nuclear steroid receptors.…”

Section: Discussionmentioning

confidence: 85%

Genome-wide coexpression of steroid receptors in the mouse brain: Identifying signaling pathways and functionally coordinated regions

Mahfouz

Lelieveldt

Grefhorst

et al. 2016

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

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Steroid receptors are pleiotropic transcription factors that coordinate adaptation to different physiological states. An important target organ is the brain, but even though their effects are well studied in specific regions, brain-wide steroid receptor targets and mediators remain largely unknown due to the complexity of the brain. Here, we tested the idea that novel aspects of steroid action can be identified through spatial correlation of steroid receptors with genome-wide mRNA expression across different regions in the mouse brain. First, we observed significant coexpression of six nuclear receptors (NRs) [androgen receptor (Ar), estrogen receptor alpha (Esr1), estrogen receptor beta (Esr2), glucocorticoid receptor (Gr), mineralocorticoid receptor (Mr), and progesterone receptor (Pgr)] with sets of steroid target genes that were identified in single brain regions. These coexpression relationships were also present in distinct other brain regions, suggestive of as yet unidentified coordinate regulation of brain regions by, for example, glucocorticoids and estrogens. Second, coexpression of a set of 62 known NR coregulators and the six steroid receptors in 12 nonoverlapping mouse brain regions revealed selective downstream pathways, such as Pak6 as a mediator for the effects of Ar and Gr on dopaminergic transmission. Third, Magel2 and Irs4 were identified and validated as strongly responsive targets to the estrogen diethylstilbestrol in the mouse hypothalamus. The brain-and genome-wide correlations of mRNA expression levels of six steroid receptors that we provide constitute a rich resource for further predictions and understanding of brain modulation by steroid hormones. neuroendocrinology | nuclear receptors | transcription regulation | estrogens | glucocorticoids S teroid receptors are part of the superfamily of nuclear receptors (NRs) that act as transcription factors regulating expression of numerous biologically important target genes (1). Their transcriptional activity is induced by steroid hormones, which respond to changed demands in terms of reproductive status, mineral balance, or stressful physical and psychological challenges. A crucial site of action is the brain, where these hormones have strong modulatory effects on physiological regulation, cognitive function, mood, and behavior. They do so by changing cellular responsiveness to a variety of neurotransmitters and peptides, and by inducing morphological changes (2, 3).Understanding the effects of steroid hormones on the brain faces the challenge to identify in as many as 900 different brain nuclei (4) both the highly cell-specific target genes that mediate the hormone effects (5, 6) and the signaling factors that mediate or influence steroid receptor signaling. The latter include proteins affecting prereceptor metabolism, interacting transcription factors (7), and downstream NR coregulator proteins (1). Even if the effects of steroid hormones are well-studied in specific regions (1, 8), overall, the brain steroid receptor targets and mediators ...

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“…From studies in animal models, only PAK4 has been found to be essential for life; Pak4 knock-out mice display severe defects in angiogenesis, in the cardiovascular system, and in neuronal development (29,30). Pak5 and Pak6 knock-out mice are viable and show few phenotypes; their double knock-out, however, is associated with cognition and locomotive defects (31,32), which are potentially associated with disruption of the interaction between two PAK substrates, Pacsin-1 and Synaptojanin-1, that normally control synaptic vesicle trafficking (33). There are clear differences between the type II PAKs in tissue expression profile (3,8,34), with PAK4 widely expressed and most abundant in prostate, testis, and colon (35), PAK5 predominantly found in the brain and pancreas (32,36), and PAK6 found largely in testis, prostate, and brain, and possibly the kidneys and placenta (34,37,38).…”

Section: Type II Paks In Signal Transductionmentioning

confidence: 99%

Signaling, Regulation, and Specificity of the Type II p21-activated Kinases

Ha¹,

Morse

Turk³

et al. 2015

Journal of Biological Chemistry

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The p21-activated kinases (PAKs) are a family of six serine/ threonine kinases that act as key effectors of RHO family GTPases in mammalian cells. PAKs are subdivided into two groups: type I PAKs (PAK1, PAK2, and PAK3) and type II PAKs (PAK4, PAK5, and PAK6). Although these groups are involved in common signaling pathways, recent work indicates that the two groups have distinct modes of regulation and have both unique and common substrates. Here, we review recent insights into the molecular level details that govern regulation of type II PAK signaling. We also consider mechanisms by which signal transduction is regulated at the level of substrate specificity. Finally, we discuss the implications of these studies for clinical targeting of these kinases.The type II PAKs 2 are members of the Sterile 20 (Ste20) family of STE (homologs of yeast Sterile 7, Sterile 11, and Sterile 20) group serine/threonine kinases. They are important for signaling from small GTPases of the RHO family, particularly the CDC42 (cell division cycle 42) and to a lesser extent RAC (Rasrelated C3 botulinum toxin substrate) isoforms, to the actin cytoskeleton and to growth and survival pathways. Type II PAKs share significant sequence similarity with the well studied type I PAKs (PAK1, PAK2, and PAK3), which are extensively reviewed elsewhere (1-5), but the roles of the type I and type II PAKs in GTPase signaling pathways, and their mechanisms of regulation, differ considerably. In the sections below, we consider the function of the type II PAK serine/threonine kinases in small GTPase pathways, the structural and biochemical basis for their regulation, mechanisms of their targeting to substrates, and some of the current strategies for targeted small molecule inhibition of these enzymes. Type II PAKs in Signal TransductionThe type II PAKs are binding partners of RHO family small GTPases. Their dominant role in signal transduction is as serine/threonine kinases, where transfer of the ␥-phosphate from an ATP molecule to a substrate protein results in consequent regulation of downstream effector pathways. The activation of type II PAK kinase signaling is associated with small GTPase binding, but as discussed below, direct activation does not seem to occur upon small GTPase binding. Rather, GTPases are thought to primarily regulate type II PAKs by controlling their subcellular localization. Type II PAKs also have reported kinase-independent roles as scaffolding proteins, with functions that are still emerging.The type II PAKs are placed at critical nodal points in multiple signaling pathways that are associated with cell growth, cytoskeletal dynamics, cell polarity, survival, and development (6 -8). They are located directly downstream of RHO family GTPase activation. Numerous substrates of type II PAKs have been identified that are thought to act as downstream effectors in distinct cellular processes. For example, direct phosphorylation of LIM kinases (9, 10), p210/␤-catenin (11, 12), slingshot phosphatase (SSH) (13), 14), and PDZ-RHOGEF (15) has...

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Targeted disruption of the Pak5 and Pak6 genes in mice leads to deficits in learning and locomotion

Cited by 93 publications

References 52 publications

Identification of neuronal substrates implicates Pak5 in synaptic vesicle trafficking

Identification of neuronal substrates implicates Pak5 in synaptic vesicle trafficking

Genome-wide coexpression of steroid receptors in the mouse brain: Identifying signaling pathways and functionally coordinated regions

Signaling, Regulation, and Specificity of the Type II p21-activated Kinases

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