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FLASH GENE

Symbol

KSR1

contributors: mct/pgu - updated : 12-01-2012

HGNC name	kinase suppressor of ras 1
HGNC id	6465

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

EXPRESSION

Rna function	widely in brain, thymuss and muscle
Type	widely

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 pharynx         Nervous nerve       highly Reproductive female system placenta     highly Urinary kidney

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Connective adipose     highly

cell lineage

cell lines

fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	one phorbol-ester/DAG-type zinc finger
	one protein kinase domain

conjugated

PhosphoP

HOMOLOGY

interspecies

ortholog to murine Ksr1

Homologene

FAMILY	protein kinase superfamily
	TKL Ser/Thr protein kinase family

CATEGORY

enzyme , regulatory

SUBCELLULAR LOCALIZATION	plasma membrane
	intracellular
	intracellular,cytoplasm
text	translocation from the cytoplasm to the cell surface in response to growth factor treatment
	recruited to the plasma membrane by Ras activation

basic FUNCTION	functions as an essential scaffolding protein to coordinate the assembly of Raf-MEK-ERK complexes
	promoting MEK and RAF phosphorylation and activity through assembly of an activated signaling complex
	positive modulator of ras-MAP kinase signaling
	molecular scaffold kinase suppressor of Ras 1 (KSR1) regulating adipogenesis
	protecting intestinal epithelium from TNF-alpha-induced apoptosis
	mitogen-activated protein (MAP) kinase scaffold that enhances the activation of the MAP kinase extracellular signal-regulated kinase (ERK)
	required for efficient NK-mediated cytolysis and polarization of cytolytic granules
	recruited to the immunological synapse during T-cell activation and membrane recruitment of KSR1 is required for recruitment of active ERK to the synapse
	plays a central role in determining the sensitivity of T-cell responses and is thus well positioned as a key control point
	required for maximal ERK activation induced by growth factors and by some cytotoxic agents
	playing a specific role in the cellular response to DNA interstrand cross-links
	likely control point used to fine-tune T-cell responses during T-cell activation and differentiation, suggesting KSR1 as a key regulator of T-cell function and plasticity
	despite a requirement for KSR1 for full ERK activation in thymocytes, full and efficient ERK activation is not essential for the majority of thymocyte selection events
	functional protein kinase capable of serine autophosphorylation and direct phosphorylation of MAP2K1
	KSR1 is a bona fide kinase whose activity is required to cooperate with RAF for the activation of MEK
	may potentially phosphorylate MEK and this phosphorylation facilitates RAF1 phosphorylation of the activation loop
	molecular scaffold of the RAF1/MEK/extracellular signal-regulated kinase (ERK) cascade that enhances oncogenic RAS signaling
	KSR1-dependent control of PPARGC1A- and ESRRA-dependent pathways that are necessary and sufficient for signaling by oncogenic HRAS to regulate metabolism and anchorage-independent growth

CELLULAR PROCESS

protein, post translation

PHYSIOLOGICAL PROCESS

text	cell-cycle control

PATHWAY

metabolism

signaling

signal transduction

RAS signal transduction

a component

KSR1, BRAF, and MEK form a ternary complex

INTERACTION

DNA

RNA

small molecule	metal binding, nucleotide,
	ATP
	ion Zn2+

protein	interacting with HSPCA/HSP90, YWHAB/14-3-3, CDC37, MAP2K/MEK, MARK3, PPP2R1A and PPP2CA
	binding RAF and MAPK/ERK, in a Ras-dependent manner
	binding to 14.3.3 proteins, prevents ths membrane localization of phosphorylated KSR1
	interacting with activated MAPK3/MAPK1 at lipid rafts for PLA2G4A activation
	modulates MAPK system sensitivity but not system output
	binds each of the three ERK cascade components to facilitate pathway activation
	MAP2K1 is a substrate of KSR1, and the catalytic activities of both proteins are required for eliciting cell survival responses downstream of TNF
	regulates endometrial sensitivity to tumor necrosis factor-related apoptosis-inducing ligand by regulating CFLAR levels

cell & other

REGULATION

activated by

EGF (epidermal growth factor)

Other	translocation regulated by CDC25C-associated kinase-1
	phosphorylated by MARK3
	dephosphorylated by PPP2CA

ASSOCIATED DISORDERS

corresponding disease(s)

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional     --over   promote high, sustained ERK activation that phosphorylates and inhibits PPARG inhibiting adipogenesis tumoral     --over   in endometrial carcinoma (

Susceptibility

Variant & Polymorphism

Candidate gene

Marker

Therapy target

ANIMAL & CELL MODELS