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FLASH GENE

Symbol

KRAS

contributors: mct - updated : 21-08-2016

HGNC name	v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog
HGNC id	6407

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Corresponding disease	CFC5 cardio-facio-cutaneous syndrome NS3 Noonan syndrome 3 SMPS2 Schimmelpenning syndrome 2
Location	12p12.1      Physical location : 25.358.179 - 25.403.854
Synonym name	oncogene KRAS2
	cellular c-ki-ras2 protooncogene
	v-Ki-ras2 Kirsten rat sarcoma 2 viral oncogene homolog
	PR310 c-K-ras oncogene
	Kirsten rat sarcoma-2 viral (v-Ki-ras2) oncogene homolog
Synonym symbol(s)	RASK2, KI-RAS, K-RAS2A, K-RAS4A, K-RAS4B, K-RAS2B, C-K-RAS, KRAS2, EVI80, KRAS1, RAS, NS

DNA

TYPE	functioning gene
STRUCTURE	45.68 kb     6 Exon(s)

MAPPING

cloned

Y

linked

Y

status

confirmed

Map	pter - D12S363 - D12S301 - (D12S1085 , IAPP , KCNJ8 , RECQL , GYS2 , D12S1066 , LDHB ) - D12S849 - (D12S1027 , D12S310 ) - D12S863 - D12S1669 - D12S1452 - D12S205 - (D12S1168E , D12S1155E ) - D12S2048 - D12S1606 - D12S1057 - D12S1435 - KRAS - D12S1134E - D12S1313 - D12S1596 - D12S1034 - cen

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_033360 6 splicing 5436 NP_203524 21 189 - 2008 18818716 also called variant a or K-RAS4A including exon 4a shares with HRAS and NRAS a post-translational modification that includes covalent attachment of a palmitoyl moiety importance in tumorigenesis, retaining a critical role in tumor relapses, for example,by supporting the self-renewal capacity of tumor-initiating cells NM_004985 5 splicing 5312 NP_004976 21 188 - 2008 18818716 also called variant b or K-RAS4B lacking exon 4a compared to variant a having C-terminal hexa-lysine motif this predominant variant b has a cds terminating in exon 4b mutation associated to severe Noonan syndrome limited to farnesylation or geranylgeranylation its hypervariable region is responsible for its specific interactions with CALM1

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 Endocrine pancreas           thyroid       highly Lymphoid/Immune lymph node       highly Nervous brain         Reproductive female system ovary     highly Urinary kidney

cell lineage

cell lines

fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains

terminating with a CAAX motif, clipped off by RCE1, an integral membrane endoprotease of the endoplasmic reticulum

HOMOLOGY

interspecies	ortholog to murine Kras
	ortholog to rattus Kras2

Homologene

FAMILY

GTP binding protein family

CATEGORY

protooncogene

SUBCELLULAR LOCALIZATION	plasma membrane
	intracellular
	intracellular,cytoplasm,organelle,mitochondria,outer
	intracellular,cytoplasm,organelle,membrane
	intracellular,nucleus,nucleolus
text	associated with the mitochondrial outer membrane
	CALM1 colocalized with KRAS mainly at the plasma membrane

basic FUNCTION	GTPase, p21 Ras (signal transduction), involved in genetic instability and apoptosis
	involved in the regulation of cell division as a result of its ability to relay external signals to the cell nucleus
	not phosphorylated, it exhibits a remarkably decreased ability to stimulate proliferation in non-saturated serum conditions
	modulates mitochondrial metabolism inbcolon cancer cells by inducing HIF1A and HIF2A target genes
	in pancreatic ductal adenocarcinoma (PDAC), oncogenic KRAS plays a critical role in coordinating the shift in Gln metabolism to maintain tumour growth and survival
	expression of KRAS and RALB and possibly RALA proteins is critical for maintaining low levels of TP53, and down-regulation of these GTPases reactivates TP53 by significantly enhancing its stability, and this contributes to suppression of malignant transformation

CELLULAR PROCESS	cell life, cell death/apoptosis

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

signal transduction

key regulator of the RAS-RAF-MEK-ERK pathway

a component	pro-apoptotic pathway linking KRAS, RASSF1 and BAX that is specifically impaired in some human tumors
	part of a novel regulatory network composed of RASSF5, the mitotic kinase Aurora A, the small GTPase KRAS, and the microtubule cytoskeleton

INTERACTION

DNA

RNA

small molecule	nucleotide,
	GTP

protein	with RAC1 and RHoA, bind to RAP1GDS1 in both active and inactive forms which requires the presence of poly-basic residues in the C-termini of the GTPases
	galectin-3 interacts with activated KRAS through the hypervariable C-terminal region and stimulates KRAS activity triggering a RAS signal that attenuates ERK, but not PI3K
	CALM1 binds to KRAS and KRAS phosphorylation inhibits its interaction with CALM1
	interaction with HIF1A nd HIF2A (HIF1A and HIF2A work together to modulate cancer metabolism and regulate genes signature overlapping with oncogenic KRAS)
	NFE2L2 interacting with KRAS and MYC (KRAS and MYC oncogenes can constitutively increase the transcription of NFE2L2 to elevate the basal activity of the antioxidant and cellular detoxification program)
	regulates BRIP1 expression to induce dissociation of BRCA1 from chromatin, inhibit DNA repair, and promote senescence
	KRAS stimulates BMP7 secretion and BMP signaling, leading to MAP3K7 activation and enhancement of Wnt-dependent transcription
	novel interplay between KRAS and HRAS, with possible implications for colorectal carcinogenesis
	FOXM1 transcription factor is a key downstream target of activated KRAS(G12D)
	critical role for the cell surface molecule CD44 in mediating cell proliferation downstream of oncogenic KRAS signaling
	KRAS regulates both CAV1 expression and other factors affecting CAV1 functions in colon cancer-derived cell migration
	RNF7 is a KRAS-cooperating oncogene that promotes lung tumorigenesis
	KRAS-AGO2 interaction is required for maximal mutant KRAS expression and cellular transformation
	LZTR1-mediated ubiquitination inhibited RAS signaling by attenuating its association with the membrane
	LZTR1 facilitates polyubiquitination and degradation of RAS-GTPases MRAS, HRAS, NRAS, and KRAS
	direct, GTP-dependent interaction between KRAS and hexokinase 1 (HK1) that alters the activity of the kinase, and thereby establish that HK1 is an effector of KRAS

cell & other

REGULATION

Other	CALM1 interaction and PKC phosphorylation is essential to regulate non-oncogenic and oncogenic KRAS activity and functionality
	phosphorylated in the presence of growth factors, or upon PKC stimulation and this phosphorylation is inhibited by CALM1 interaction
	posttranslational modification of KRAS: acetylation on lysine 104 (K104), that modulates KRAS activity by interfering with GEF-induced nucleotide exchange

ASSOCIATED DISORDERS

corresponding disease(s)

NS3 , CFC5 , SMPS2

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral somatic mutation       in non small cell lung adenocarcinomas, in pancreatic cancer, in endometrial carcinoma (not in endometrial hyperplasia)and in thyroid cancer with poor prognosis tumoral somatic mutation       in MM and PPCL at an early stage, in rectal cancer and adenoma, and in colorectal tumors with poor prognosis tumoral somatic mutation       in high hyperdiploid childhood acute lymphoblastic leukemia tumoral somatic mutation       promotes colon cancer progression (mutation arise after loss of APC during colon cancer progression) tumoral somatic mutation       in colorectal cancer is correlated with increased proliferation and spontaneous apoptosis tumoral somatic mutation     gain of function activating mutations in the KRAS gene impair the ability of the KRAS protein to switch between active and inactive states, leading to cell transformation and increased resistance to chemotherapy and biological therapies targeting epidermal growth factor receptor tumoral somatic mutation     gain of function activating KRAS mutations is significantly correlated to an upregulation of 13 genes among them DUSP4, a MAP-kinase phosphatase, and SMYD3 in colorectal cancer tumoral somatic mutation       in autoimmune lymphoproliferative syndrome constitutional     --low   depletion of KRAS promotes proteasome degradation of BIRC5 (PMID

Susceptibility

Variant & Polymorphism

Candidate gene
Marker
Therapy target
	System Type Disorder Pubmed cancer digestive colon importance of KRAS alterations as a potential therapeutic target for Colorectal cancer osteoarticular     RAS/ERK1/2 inhibition could be a potent strategy to treat RASopathies, including Noonan sdr cancer digestive pancreas therapy target in pancreatic ductal adenocarcinoma (PDAC)

ANIMAL & CELL MODELS