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FLASH GENE

Symbol

PAK1

contributors: mct/npt/pgu - updated : 27-09-2019

HGNC name	p21 protein (Cdc42/Rac)-activated kinase 1
HGNC id	8590

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Corresponding disease	MCSZ2 microcephaly, seizures, and developmental delay 2
Location	11q14.1      Physical location : 77.033.060 - 77.185.108
Synonym name	p21/Cdc42/Rac1-activated kinase 1 (yeast Ste20-related)
	p21/Cdc42/Rac1-activated kinase 1 (STE20 homolog, yeast)
	STE20 homolog, yeast
Synonym symbol(s)	PAKalpha, MGC130000, MGC130001, Alpha-PAK
EC.number	2.7.11.1

DNA

TYPE	functioning gene
STRUCTURE	152.05 kb     15 Exon(s)

10 Kb 5' upstream gene genomic sequence study

MAPPING

cloned

Y

linked

N

status

provisional

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_001128620 - - 3484 NP_001122092 - 553 - 2007 18006851 NM_002576 15 - 3435 NP_002567 - 545 - 2007 18006851

EXPRESSION

Type	ubiquitous

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Digestive mouth tongue     highly Endocrine thyroid       highly Nervous brain         Respiratory respiratory tract larynx     highly

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Nervous central

cell lineage

cell lines

fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains

a GBD domain

mono polymer

homomer , dimer , trimer

HOMOLOGY

interspecies	homolog to yeast S.cerevisiae Ste20 related
	homolog to murine Pak1
	homolog to C.elegans c09b8.7

Homologene

FAMILY	group I of the PAK family
	STE Ser/Thr protein kinase family
	STE20 subfamily

CATEGORY

enzyme , regulatory

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,cytoplasm,organelle,Golgi
	intracellular,cytoplasm,cytosolic
	intracellular,cytoplasm,cytoskeleton,microtubule,centrosome
	intracellular,nucleus
text	localized to centrosomes

basic FUNCTION	p21/Cdc42/Rac1-activated kinase 1, serine/threonine kinase
	downstream effector linking Rho GTPases to actin cytoskeleton
	potentially involved in the regulation of a subset of cytoskeletal dynamics initiated by chemoattractant and phagocytic stimuli in human neutrophils
	plays a crucial role in lamellipodia formation, and is at the interface between junction destabilization and increased motility during morphogenetic events
	regulates the activation of Aurora A during mitosis
	serine/threonine kinase implicated in regulation of cell motility and survival and in malignant transformation of mammary epithelial cells
	cooperate with PAK2, PAK3 kinase, and CHL1, most likely in independent pathways, in regulating morphological development of the leading process/apical dendrite of embryonic cortical neurons
	plays a fundamental role in controlling cell motility by linking a variety of extracellular signals to changes in actin cytoskeleton organization, cell shape, and adhesion dynamics
	a novel and crucial role for PAK1 and CDH1 endocytosis in determining lumen size and shape, and also identify a mechanism for multiple lumen formation, a poorly understood process that occurs in salivary gland normal embryonic development and pathological conditions
	having functions in novel signaling pathways in NF2
	essential role of PAK1 and PAK3 in coordinating neuronal complexity and synaptic properties, suggesting the critical importance of dendrite/axon growth in dictating postnatal brain growth and attainment of normal brain size and function
	implicated in signaling by growth factor receptors and morphogenetic processes that control cell polarity, invasion, and actin cytoskeleton organization
	essential role of PAK1 and PAK3 in coordinating neuronal complexity and synaptic properties
	critical molecule coordinating cytoskeletal systems for efficient cell migration
	kinase activity of PAK1 is necessary for PAK1-induced transformation
	PAK1 and PAK3 belong to group I of the PAK family and control cell movement and division
	PAK3 and PAK1 signaling may be coordinated by heterodimerization
	physiological role of PAK1-INPP5K binding in the regulation of insulin signaling in skeletal muscle
	GIT1/ARHGEF7 signaling proteins with PAK1 kinase represent a novel regulatory mechanism of microtubule nucleation in interphase cells
	key regulator of actin dynamics, cell proliferation and cell survival
	has an anti-arrhythmic and anti-hypertrophic, protective function
	important role of PAK1 in controlling postnatal brain development and attaining a normal brain volume
	PAK2, but not PAK1, regulates contraction-stimulated skeletal muscle glucose transport
	regulate processes associated with cytoskeletal rearrangements, such as cell division, adhesion, and migration

CELLULAR PROCESS

cell communication

PHYSIOLOGICAL PROCESS

text	regulating cell mobility and morphology

PATHWAY

metabolism

signaling

signal transduction

	JNK1 cascade (Jun N -terminal kinase MAP kinase pathway
	PAK1-MORC2 axis is likely critical for orchestrating the interplay between chromatin dynamics and the maintenance of genomic integrity through sequentially integrating multiple essential enzymatic processes
	synapse formation mediated by EPHB1/DLG3/PAK1 signaling in the early postnatal brain may be crucial for cognitive development

a component	could form an heterotrimeric complex with PPM1E and PPM1F
	KIF3A-PAK1 signaling coordinates planar polarization of the hair bundle and the basal body in hair cells
	AKT1-PAK1-AJUBA feedback loop integrates spatiotemporal signaling with actin remodeling at cell-cell contacts and stabilizes preassembled cadherin complexes

INTERACTION

DNA

RNA

small molecule

protein	GTP bound cdc 42/p21
	Rac1
	PAK1IP1 binding
	strong direct interaction of PGM1 with PAK1, and PAK1-mediated phosphorylation of PGM1 selectively on threonine 466 significantly increased PGM enzymatic activity
	GIT2 has been implicated in regulating cell spreading and motility through its transient recruitment of the p21-activated kinase (PAK1) to focal adhesions
	binding to Scrib-ARHGEF7-GIT1 complex
	interacting with CDC2L2 (PAK1 may serve as a downstream effector of CDC2L2 during mitosis progression)
	cooperate with DYNLL1 in malignant transformation of breast cancer cells (DYNLL1 facilitates nuclear import of PAK1, function indispensable during vertebrate development)
	Rac effector PAK1 transiently activated upon cell-cell adhesion and directly phosphorylated AJUBA (Thr172)
	simultaneously activates MAPK and MET signaling; the latter via inhibition of merlin
	STRADA regulates PAK1 in STK11-null cells to oversee cancer cell polarity and invasion
	inhibits the activity of PAK3a but not of the splice variant PAK3b in a trans-regulatory manner
	interacts with WNT signaling to regulate tissue polarity and gene expression
	PAK1 interacts with phospholipid membrane domains via E-Syt2, where it may cooperate in the SYT2-dependent endocytosis of activated FGFR1 by modulating cortical actin stability
	NCAM1 interacts with PAK1 in growth cones of neurons
	DLG3 has unique roles in cortical synapse development by mediating EPHB1 and its downstream PAK1 signaling pathway
	PAK1 can stimulate MAP2K1/MAP2K2 activity in a kinase-independent manner, probably by serving as a scaffold to facilitate interaction of RAF1
	ARHGAP15, is a substrate of the Rac effectors PAK1 and PAK2
	CSNK2A1 is an upstream activating kinase of PAK1, providing a novel mechanism for PAK1 activation
	ARHGEF7 and GIT1 are required for synaptic GABA(A)R surface stability through the activity of the GTPase RAC1 and downstream effector PAK1
	INPP5K interacts with PAK1 and glucose-regulated protein 78 (HSPA5), both of which are necessary for the regulation of insulin signaling
	PAK1 expression is regulated by NUDT21 through its 3'-UTR alternative polyadenylation (APA)

cell & other

REGULATION

activated by	cdc42/p21
	rac1
	autophosphorylation
	DSCAM
	CSNK2A1, that is an upstream activating kinase of PAK1, providing a novel mechanism for PAK1 activation

inhibited by	binding to PAK1IP1
	PPM1F and PPM1E

ASSOCIATED DISORDERS

corresponding disease(s)

MCSZ2

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral       gain of function in breast cancer tumoral     --over   in ovarian, breast, and bladder cancers

Susceptibility

Variant & Polymorphism

Candidate gene
Marker
Therapy target
	System Type Disorder Pubmed neurology     may serve as a useful therapeutic target in NF2 cancer reproductive breast PAK1-directed therapy in breast cancer cancer lung   evidence for potential antitumor efficacy of PAK1 inhibition in squamous nonsmall cell lung carcinomas

ANIMAL & CELL MODELS