KSR1 (kinase suppressor of ras 1)

2011-02-01 Mario Fernandez , Robert Lewis Affiliation

Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, NE 68198, USA

Identity

HGNC

KSR1

LOCATION

17q11.1

LOCUSID

8844

ALIAS

KSR,RSU2

FUSION GENES

Show Gene Fusions

DNA/RNA

KSR1 contains 17 exons, 154426 base pairs.

Description

The KSR1 gene was discovered in D. melanogaster and is highly conserved along the evolutionary tree through H. sapiens.

Transcription

Transcription can produce two different mRNA transcripts. The KSR1 is expressed in the thymus, bone marrow, brain, heart, kidney, lung, liver, pancreas, mammary gland, ovary, testis and muscle.

Pseudogene

No known pseudogenes.

Proteins

Note

Belongs to the KSR family of proteins.

The KSR1 protein contains five conserved areas (CA). The CA1 region is unique to KSR1 protein; the CA2 region is a proline-rich region; the CA3 region is implicated in the Ras-induced plasma membrane localization; the CA4 region is a serine/threonine rich region and contains the MAPK docking site (FXFP); and the putative kinase domain (CA5), which contains an amino acid variation in subdomain II that suggests that this protein is catalytically inert. The KSR1 protein is composed of 921 amino acids.

Description

The KSR1 protein is 921 kDa. There have been 15 phosphorylation sites identified.

Expression

Brain, kidney, lung, pancreas, ovaries, testis, breast.

Localisation

Sequestered in the cytoplasm in quiescents cells. Upon stimulation, KSR1 protein localizes to the plasma membrane.

Function

Acts as a scaffold for the Raf/MEK/ERK kinase cascade.

Homology

R. norvegicus KSR1 (91.85%), M. musculus KSR1 (91.3%), C. familians KSR1 (93.62%), G. gallus KSR1 (76.39%), D. reno KSR1 (67.85%), D. Melanogaster KSR (41.06%), C. elegans KSR1 (35.37%), X. laevis KSR1 (76.06%).

Mutations

Note

There have been no prominent germinal or somatic mutations identified.

Implicated in

Entity name

Cancer

Note

KSR1 has not been found to be upregulated or downregulated in tumors. However, studies in KSR1 knockout mice showed that the mice were less susceptible to papilloma virus driven tumors, indicating that KSR1 is required for Ras-mediated oncogenesis.

Article Bibliography

Pubmed ID	Last Year	Title	Authors
19114553	2009	Ras subcellular localization defines extracellular signal-regulated kinase 1 and 2 substrate specificity through distinct utilization of scaffold proteins.	Casar B et al
18332145	2008	IMP modulates KSR1-dependent multivalent complex formation to specify ERK1/2 pathway activation and response thresholds.	Chen C et al
17056543	2006	The MAPK scaffold kinase suppressor of Ras is involved in ERK activation by stress and proinflammatory cytokines and induction of arthritis.	Fusello AM et al
12133899	2002	Expression of kinase suppressor of Ras in the normal adult and embryonic mouse.	Giblett SM et al
19139278	2009	The mitogen-activated protein kinase scaffold KSR1 is required for recruitment of extracellular signal-regulated kinase to the immunological synapse.	Giurisato E et al
15899786	2005	Expression of kinase suppressor of Ras1 enhances cisplatin-induced extracellular signal-regulated kinase activation and cisplatin sensitivity.	Kim M et al
8521514	1995	The ksr-1 gene encodes a novel protein kinase involved in Ras-mediated signaling in C. elegans.	Kornfeld K et al
16107706	2005	The molecular scaffold kinase suppressor of Ras 1 (KSR1) regulates adipogenesis.	Kortum RL et al
16507997	2006	The molecular scaffold kinase suppressor of Ras 1 is a modifier of RasV12-induced and replicative senescence.	Kortum RL et al
15121859	2004	The molecular scaffold KSR1 regulates the proliferative and oncogenic potential of cells.	Kortum RL et al
15240686	2004	Kinase suppressor of Ras couples Ras to the ERK cascade during T cell development.	Laurent MN et al
12874031	2003	Deficiency of kinase suppressor of Ras1 prevents oncogenic ras signaling in mice.	Lozano J et al
17613518	2007	Caspase-dependent cleavage disrupts the ERK cascade scaffolding function of KSR1.	McKay MM et al
19541618	2009	Signaling dynamics of the KSR1 scaffold complex.	McKay MM et al
9371754	1997	KSR stimulates Raf-1 activity in a kinase-independent manner.	Michaud NR et al
10891492	2000	Identification of B-KSR1, a novel brain-specific isoform of KSR1 that functions in neuronal signaling.	Müller J et al
11741534	2001	C-TAK1 regulates Ras signaling by phosphorylating the MAPK scaffold, KSR1.	Müller J et al
11940661	2002	Kinase suppressor of Ras (KSR) is a scaffold which facilitates mitogen-activated protein kinase activation in vivo.	Nguyen A et al
12932319	2003	Protein phosphatase 2A positively regulates Ras signaling by dephosphorylating KSR1 and Raf-1 on critical 14-3-3 binding sites.	Ory S et al
19727074	2009	A dimerization-dependent mechanism drives RAF catalytic activation.	Rajakulendran T et al
19147494	2009	KSR1 is required for cell cycle reinitiation following DNA damage.	Razidlo GL et al
17174095	2007	CK2 Is a component of the KSR1 scaffold complex that contributes to Raf kinase activation.	Ritt DA et al
11850406	2002	KSR is a scaffold required for activation of the ERK/MAPK module.	Roy F et al
15684389	2005	Nm23-H1 metastasis suppressor expression level influences the binding properties, stability, and function of the kinase suppressor of Ras1 (KSR1) Erk scaffold in breast carcinoma cells.	Salerno M et al
8521513	1995	The C. elegans ksr-1 gene encodes a novel Raf-related kinase involved in Ras-mediated signal transduction.	Sundaram M et al
8946910	1996	KSR modulates signal propagation within the MAPK cascade.	Therrien M et al
12960962	2003	Pharmacologic inactivation of kinase suppressor of ras-1 abrogates Ras-mediated pancreatic cancer.	Xing HR et al
15520859	2004	Kinase suppressor of Ras-1 protects intestinal epithelium from cytokine-mediated apoptosis during inflammation.	Yan F et al

Other Information

Locus ID:

NCBI: 8844
MIM: 601132
HGNC: 6465
Ensembl: ENSG00000141068

Variants:

dbSNP: 8844
ClinVar: 8844
TCGA: ENSG00000141068
COSMIC: KSR1

RNA/Proteins

Gene ID	Transcript ID	Uniprot
ENSG00000141068	ENST00000268763	A0A0A0MQW1
ENSG00000141068	ENST00000398982	A8MY87
ENSG00000141068	ENST00000398988	Q8IVT5
ENSG00000141068	ENST00000509603	Q8IVT5
ENSG00000141068	ENST00000577823	J3QLI1
ENSG00000141068	ENST00000580430	J3QQL4
ENSG00000141068	ENST00000582410	J3QSG8
ENSG00000141068	ENST00000583370	J3QR75
ENSG00000141068	ENST00000644418	A0A2R8Y4X0
ENSG00000141068	ENST00000644974	A0A2R8Y5H9

Expression (GTEx)

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Pathways

Pathway	Source	External ID
Tuberculosis	KEGG	ko05152
Tuberculosis	KEGG	hsa05152
Ras signaling pathway	KEGG	hsa04014
Disease	REACTOME	R-HSA-1643685
Diseases of signal transduction	REACTOME	R-HSA-5663202
Immune System	REACTOME	R-HSA-168256
Innate Immune System	REACTOME	R-HSA-168249
DAP12 interactions	REACTOME	R-HSA-2172127
DAP12 signaling	REACTOME	R-HSA-2424491
RAF/MAP kinase cascade	REACTOME	R-HSA-5673001
RAF activation	REACTOME	R-HSA-5673000
MAP2K and MAPK activation	REACTOME	R-HSA-5674135
Negative regulation of MAPK pathway	REACTOME	R-HSA-5675221
Fc epsilon receptor (FCERI) signaling	REACTOME	R-HSA-2454202
FCERI mediated MAPK activation	REACTOME	R-HSA-2871796
Cytokine Signaling in Immune system	REACTOME	R-HSA-1280215
Signaling by Interleukins	REACTOME	R-HSA-449147
Interleukin-2 signaling	REACTOME	R-HSA-451927
Interleukin receptor SHC signaling	REACTOME	R-HSA-912526
Interleukin-3, 5 and GM-CSF signaling	REACTOME	R-HSA-512988
Signal Transduction	REACTOME	R-HSA-162582
Signaling by EGFR	REACTOME	R-HSA-177929
GRB2 events in EGFR signaling	REACTOME	R-HSA-179812
SHC1 events in EGFR signaling	REACTOME	R-HSA-180336
Signaling by Insulin receptor	REACTOME	R-HSA-74752
Insulin receptor signalling cascade	REACTOME	R-HSA-74751
IRS-mediated signalling	REACTOME	R-HSA-112399
SOS-mediated signalling	REACTOME	R-HSA-112412
Signalling by NGF	REACTOME	R-HSA-166520
NGF signalling via TRKA from the plasma membrane	REACTOME	R-HSA-187037
Signalling to ERKs	REACTOME	R-HSA-187687
Signalling to RAS	REACTOME	R-HSA-167044
Signalling to p38 via RIT and RIN	REACTOME	R-HSA-187706
Prolonged ERK activation events	REACTOME	R-HSA-169893
Frs2-mediated activation	REACTOME	R-HSA-170968
ARMS-mediated activation	REACTOME	R-HSA-170984
Signaling by PDGF	REACTOME	R-HSA-186797
Downstream signal transduction	REACTOME	R-HSA-186763
Signaling by VEGF	REACTOME	R-HSA-194138
VEGFA-VEGFR2 Pathway	REACTOME	R-HSA-4420097
VEGFR2 mediated cell proliferation	REACTOME	R-HSA-5218921
Signaling by SCF-KIT	REACTOME	R-HSA-1433557
MAPK family signaling cascades	REACTOME	R-HSA-5683057
MAPK1/MAPK3 signaling	REACTOME	R-HSA-5684996
Signaling by GPCR	REACTOME	R-HSA-372790
Gastrin-CREB signalling pathway via PKC and MAPK	REACTOME	R-HSA-881907
Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R)	REACTOME	R-HSA-2404192
IGF1R signaling cascade	REACTOME	R-HSA-2428924
IRS-related events triggered by IGF1R	REACTOME	R-HSA-2428928
Signaling by Leptin	REACTOME	R-HSA-2586552
Developmental Biology	REACTOME	R-HSA-1266738
Axon guidance	REACTOME	R-HSA-422475
NCAM signaling for neurite out-growth	REACTOME	R-HSA-375165
RET signaling	REACTOME	R-HSA-8853659
Oncogenic MAPK signaling	REACTOME	R-HSA-6802957
Signaling by RAS mutants	REACTOME	R-HSA-6802949
Signaling by high-kinase activity BRAF mutants	REACTOME	R-HSA-6802948
Signaling by moderate kinase activity BRAF mutants	REACTOME	R-HSA-6802946
Paradoxical activation of RAF signaling by kinase inactive BRAF	REACTOME	R-HSA-6802955
Signaling by BRAF and RAF fusions	REACTOME	R-HSA-6802952

Protein levels (Protein atlas)

Not detected

Low

Medium

High

References

Pubmed ID	Year	Title	Citations
36493900	2023	SHP2 inhibition mitigates adaptive resistance to MEK inhibitors in KRAS-mutant gastric cancer through the suppression of KSR1 activity.	2
37511580	2023	Kinase Suppressor of RAS 1 (KSR1) Maintains the Transformed Phenotype of BRAFV600E Mutant Human Melanoma Cells.	0
37972068	2023	SOS1 and KSR1 modulate MEK inhibitor responsiveness to target resistant cell populations based on PI3K and KRAS mutation status.	2
36493900	2023	SHP2 inhibition mitigates adaptive resistance to MEK inhibitors in KRAS-mutant gastric cancer through the suppression of KSR1 activity.	2
37511580	2023	Kinase Suppressor of RAS 1 (KSR1) Maintains the Transformed Phenotype of BRAFV600E Mutant Human Melanoma Cells.	0
37972068	2023	SOS1 and KSR1 modulate MEK inhibitor responsiveness to target resistant cell populations based on PI3K and KRAS mutation status.	2
33461174	2021	Praja2 suppresses the growth of gastric cancer by ubiquitylation of KSR1 and inhibiting MEK-ERK signal pathways.	6
33461174	2021	Praja2 suppresses the growth of gastric cancer by ubiquitylation of KSR1 and inhibiting MEK-ERK signal pathways.	6
30917119	2019	Kinase suppressor of Ras 1 and Exo70 promote fatty acid-stimulated neurotensin secretion through ERK1/2 signaling.	5
30917119	2019	Kinase suppressor of Ras 1 and Exo70 promote fatty acid-stimulated neurotensin secretion through ERK1/2 signaling.	5
29433126	2018	MEK drives BRAF activation through allosteric control of KSR proteins.	68
29596465	2018	Homozygous KSR1 deletion attenuates morbidity but does not prevent tumor development in a mouse model of RAS-driven pancreatic cancer.	2
29980571	2018	Erbin Suppresses KSR1-Mediated RAS/RAF Signaling and Tumorigenesis in Colorectal Cancer.	17
29433126	2018	MEK drives BRAF activation through allosteric control of KSR proteins.	68
29596465	2018	Homozygous KSR1 deletion attenuates morbidity but does not prevent tumor development in a mouse model of RAS-driven pancreatic cancer.	2

Citation

Mario Fernandez ; Robert Lewis

KSR1 (kinase suppressor of ras 1)

Atlas Genet Cytogenet Oncol Haematol. 2011-02-01

Online version: http://atlasgeneticsoncology.org/gene/41107/ksr1-(kinase-suppressor-of-ras-1)