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FLASH GENE

Symbol

SUFU

contributors: shn/npt - updated : 17-11-2017

HGNC name	suppressor of fused homolog (Drosophila)
HGNC id	16466

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Corresponding disease	JBTS32 Joubert syndrome 32 MDB medulloblastoma, SUFU related NBCCS3 nevoid basal cell carcinoma syndrome 3
Location	10q24.32      Physical location : 104.263.718 - 104.393.214
Synonym name	likely ortholog of mouse suppressor of fused homolog (Drosophila)
Synonym symbol(s)	SUFUH, SUFUXL, PRO1280, JBTS32, PRO1280H

DNA

TYPE	functioning gene
STRUCTURE	129.49 kb     12 Exon(s)

10 Kb 5' upstream gene genomic sequence study

MAPPING

cloned

Y

linked

N

status

provisional

Map	cen - D10S1710 - D10S1240 - SUFU - D10S1697 - D10S1267 - qter

RNA

TRANSCRIPTS	type	messenger

text	encodes a component of the Sonic hedgehog signaling pathway miR378 targets sequence in the 3-prime UTRs of SUFU transcript and miR378 downregulates its expression

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_001178133 11 - 1900 NP_001171604 - 433 - 2001 1155703 SUFUv2 NM_016169 12 - 4894 NP_057253 - 484 - 2001 1155703 SUFUv1 variant 3 10 - 2673 isoform 3 - 481 - 2001 1155703 SUFUvN 13 - - - - detected in Pancreatic ductal adenocarcinoma (PDAC) tissue 2016 27840902 sequence of the new protein-coding exon was the same as a fragment of intron between exon 10 and 11 of SUFUv1 SUFU isoform N novel transcript variant of SUFU which can be transcribed and translated into corresponding protein and its transcription is related with metastasis of lymph nodes in PDAC

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 Cardiovascular heart       highly Digestive intestine large intestine colon   lowly   liver       highly Endocrine pancreas       highly Lymphoid/Immune spleen       highly Nervous brain       highly Reproductive female system placenta     highly   female system ovary     highly   male system prostate     highly   male system testis     highly Respiratory lung       highly Urinary kidney       highly

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Muscular striatum skeletal   highly

cell lineage

cell lines

fluid/secretion

at STAGE

physiological period

embryo

Text	highly expressed in osteoblasts in the perichondrium during human embryonic bone formation

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	a high-scoring PEST domain
	a N-terminal globular domain
	four consensus protein kinase A (PKA) recognition sites

HOMOLOGY

interspecies	ortholog to Sufu, Mus musculus
	homolog to Drosophila (sufu)
	ortholog to SUFU, Pan troglodytes
	ortholog to Sufu, Rattus norvegicus
	ortholog to sufu, danio rerio

Homologene

FAMILY

SUFU family

CATEGORY

adaptor , regulatory , transcription factor , tumor suppressor

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,cytoplasm,cytosolic
	intracellular,cytoplasm,cytoskeleton,microtubule
	intracellular,nucleus
text	GLIS3 and SUFU co-localize to the nucleus
	on a cellular level, endogenous SUFU can mainly be detected in the cytoplasm and the nucleus

basic FUNCTION	is a key negative regulator in the vertebrate Hedgehog signaling pathway
	inhibiting the GLI-1 transcriptal activator in Hedgehog signaling pathway and hegative regulator of HH signaling
	serving as an adaptor linking GLI to the SLIMB-dependent proteasomal degradation pathway
	inhibiting osteogenic differentiation in response to signalling from sonic Hedgehog
	controls protein levels of full-length GLI1, GLI2, GLI3 transcription factors, thus affecting the production of GLI activators and repressors essential for graded Hh responses
	predisposing to medulloblastoma by modulating the SHH signaling pathway
	prevent the nuclear transportation of GLIs (GLI1, GLI2, GLI3), as well as to promote their processing
	Sufu degradation through the ubiquitin–proteasome pathway is promoted by Sonic hedgehog (Shh)
	controls cerebellar patterning and cell differentiation in a GLI3 repressor-dependent manner
	potential role for SUFU in the modulation of different aspects of the GLIS3 signaling pathway, including the transcriptional regulation of target genes and protein stability
	major negative regulator of the Hh-signaling pathway
	SUFU and KIF7 are crucial components in the regulation of GLI2 localization and activity, illustrating their overlapping functions in skin development and tumor suppression
	essential repressor of SHH signaling pathway
	controlling protein levels of all three GLI genes by SUFU is a conserved mechanism to modulate HH responses albeit via distinct pathways
	plays a conservative role in the regulation of the GLI transcription factors within the Hedgehog (Hh) signaling pathway
	controls cerebellar neuronal differentiation in a manner modulated by GLI3 repressor and FGF19
	tissue development is differentially affected in response to the reduced SUFU levels, providing novel insight regarding the requirements of different levels of SUFU for proper organogenesis
	the canonical role of SUFU as an inhibitor of SHH signaling is conserved at later stages of corticogenesis and SUFU plays a crucial role in regulating neuronal number by controlling the cell cycle dynamics of intermediate progenitor (IP) cells in the embryonic neocortex

CELLULAR PROCESS	nucleotide, transcription, regulation
	protein, degradation

PHYSIOLOGICAL PROCESS

development

text	skeletal development
	nucleocytoplasmic transport of GLI-1

PATHWAY

metabolism

signaling

Hedgehog signalling pathway

a component

MYCBP forms a complex with GLI and SUFU without HH stimulation but remains inactive

INTERACTION

DNA

RNA

small molecule

protein	zinc-finger transcription factor Gli
	GLI1 transcriptional activator
	GLI2 and GLI3
	SLIMB, F-box containing protein
	interacting with ULK3 through its kinase domain (KD)
	interacting with SPOP and GLI1, GLI2, GLI3 (SUFU regulates GLI protein levels by antagonizing the activity of SPOP, a conserved GLI-degrading factor) (physically interacts with SUFU, and the ULK3-SUFU complex is sensitive to SHH signaling)
	interacting with GLIS3 (GLIS3 promoted the nuclear accumulation of SUFU)
	RAB23 directly associates with SUFU and inhibits GLI1 function in a SUFU-dependent manner
	PTHLH regulates chondrocyte differentiation and GLI activity in a SUFU-dependent manner, with SUFU acting as a molecular switch in its regulation of differentiation
	KIF7 is required to establish high intracellular GLI activity by antagonizing the SUFU-inhibition of GLI2
	RIOK3 is a novel modulator of SUFU subcellular distribution
	TTC26 is necessary for efficient coupling between the accumulation of GLI at the ciliary tip and its dissociation from SUFU
	SUFU recruits GATAD2B to block GLI-mediated HH target gene expression
	perturbations of SUFU and KIF7 affect GLI activity and recapitulate the full spectrum of vertebrate limb defects, ranging from severe truncation to polydactyly
	SUFU is involved in the genetic network that restricts the posterior expression of GLI2/3/HAND2 and GREMLIN/FGF in limb bud patterning
	NEK2 is found to stabilize SUFU at least partly depending on its kinase activity, thereby triggering phosphorylation of the SUFU protein
	RUSC1 and RUSC2 interact with SUFU and restrict the response of cells to HH signaling
	NEK2 stabilizes SUFU through impairing ubiquitin/proteasome degradation of SUFU
	BCL2 proteins directly promote SUFU turnover, inhibit SUFU-GLI interaction, and induce the expression of the GLI target genes BCL2, MCL1 and BCL2L1

cell & other

REGULATION

Other

factors modulating the nucleo-cytoplasmic distribution of SUFU impact on the normal function of this tumor suppressing protein

ASSOCIATED DISORDERS

corresponding disease(s)

MDB , NBCCS3 , JBTS32

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral       loss of function in medulloblastoma and skin tumor tumoral somatic mutation       in basal cell carcinoma (BCC) of the skin tumoral germinal mutation       predispose to meningiomas, particularly to multiple meningiomas constitutional germinal mutation       can result in neural tube defects

Susceptibility

associated with cancer-predisposing syndromes: basal cell nevus syndrome to NTDs (Neural tube defects) and encephalocele

Variant & Polymorphism other	SUFU mutations predispose to meningiomas in addition to medulloblastomas
	rs10786691 A>G polymorphism may be a potential risk factor for NTDs and encephalocele

Candidate gene

Marker

Therapy target

ANIMAL & CELL MODELS

	mouse deleted for Sufu gene led to lethality at embryonic day 9.5 with cephalic and neural tube defects. Mice heterozygous for Sufu deletion are normal and fertile but develope a skin phenotype with basaloid changes and jaw keratocysts (Svard et al, 2006)
	mutant mice lacking Sufu show excessive pathway activity and die as embryos with patterning defects