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FLASH GENE

Symbol

SMO

contributors: mct/pgu - updated : 28-08-2020

HGNC name	smoothened homolog (Drosophila)
HGNC id	11119

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Corresponding disease	CJS Curry-Jones syndrome PHLS
Location	7q32.1      Physical location : 128.828.712 - 128.853.383
Synonym name	smoothened
	seven transmembrane helix receptor
	Gx protein
	frizzled family member 11
	seven transmembrane helix receptor
Synonym symbol(s)	SMOH, Gx, FZD11

DNA

TYPE	functioning gene
STRUCTURE	24.67 kb     12 Exon(s)

10 Kb 5' upstream gene genomic sequence study

MAPPING

cloned

Y

linked

N

status

confirmed

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_005631 12 - 3772 NP_005622 86.2 787 - 1998 9628830

EXPRESSION

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 Cardiovascular heart         Hearing/Equilibrium ear inner cochlea   highly Nervous brain limbic system hippocampus     Rattus norvegicus Fetal   brain limbic system hippocampus     Rattus norvegicus Adult   brain hindbrain cerebellum   highly Rattus norvegicus Adult   brain hindbrain cerebellum     Rattus norvegicus Fetal Reproductive female system ovary     highly   female system breast mammary gland       male system testis       Homo sapiens Urinary kidney

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Blood / hematopoietic bone marrow       Connective bone       Muscular striatum skeletal

cells

System Cell Pubmed Species Stage Rna symbol Nervous neuron Rattus norvegicus Nervous Purkinje cell Rattus norvegicus Reproductive spermatocyte Homo sapiens

cell lineage

cell lines

fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	seven transmembrane segments spanning protein
	one frizzled (FZ) domain
	two extracellular loops EC1 and EC2, playing a regulatory role in control of Hedgehog pathway activation
	Smo auto-inhibitory domain (SAID domain, Smo C-tail amino acids 661–818) contains several arginine motifs, which can block the phosphorylation of their adjacent target sites

secondary structure

heptahelical structure required for binding of cyclopamine that is the target for ortho- and allosteric G protein–coupled receptor (GPCR) modulators

HOMOLOGY

interspecies	homolog to Drosophila segment polarity gene Smoothened
	homolog to rattus Smo (93.6pc)
	homolog to murine Smo (93.4pc)

Homologene

FAMILY	G-protein coupled receptor Fz/Smo family
	class F family of G-protein coupled receptors

CATEGORY

regulatory , protooncogene , receptor membrane G

SUBCELLULAR LOCALIZATION	extracellular
	plasma membrane
	intracellular
	intracellular,cytoplasm,cytoskeleton,microtubule

basic FUNCTION	positive regulator of HH signaling pathway
	G protein-coupled receptor probably associated with the patched protein (PTCH) to transduce the hedgehog's proteins signal
	involved in the primary cilium
	serpentine receptor
	PTCH1 and SMO are present in the processes and growth cones of immature neurons
	as a membrane protein of HH pathway central components, SMO plays a crucial role in transducing the HH signal across the cell plasma membrane
	SMO is likely ubiquitylated in the absence of HH, and then recognized by VPS36 for its trafficking and endocytosis
	is the essential transducer of Sonic hedgehog (Shh) signaling, which regulates cell fate and proliferation during embryogenesis
	likely the highest levels of vertebrate Hedgehog signaling activity require efficient SMO ciliary enrichment
	encodes a G protein-coupled receptor that functions in Hedgehog signal transduction, an essential step during eye development
	contribute to the maintenance of healthy ocular development
	potential function of SMO in regulating basal ciliary trafficking of GLI2 when the pathway is off

CELLULAR PROCESS

PHYSIOLOGICAL PROCESS

development

text	regulating of left-right (L/R) asymetry

PATHWAY

metabolism

signaling

signal transduction

	SHH signaling pathway
	SMO signaling, acting through CCND2, is critical for the proper development and maturation of the neocortex

a component

critical component of the Hedgehog (Hh) signaling pathway

INTERACTION

DNA

RNA

small molecule

protein	interacting normally with PTCH
	activating GLI1
	interaction with KIF3A is mediated by beta-arrestins
	Sertoli cells coordinate DHH-dependent spermatogenesis events via PTCH1 and SMO prior to the first meiotic division and in postmeiotic (haploid) cells, particularly during the first half of spermiogenesis
	USP8 interacting with SMO (overexpression of USP8 prevents SMO ubiquitination and elevates SMO accumulation, leading to increased HH signaling activity)
	EVC/EVC2 complex interacts with SMO and is required for signal transduction events
	SMO activates trimeric G proteins and CARD11-associated signaling complex, leading to NFKB1 activation, contributing to the survival of DLBCL
	ESCRT-II complex, especially VPS36, has a special role in controlling HH signaling by targeting the membrane protein SMO for its trafficking in the absence of HH, thereby regulating HH signaling activity
	in the absence of HH, VPS36 interacts with ubiquitylated SMO, thereby negatively regulating the accumulation of SMO on plasma membrane
	interaction between SMO and VPS36 is mediated by the VPS36 GLUE domain, and regulated by the HH signal and SMO C-tail phosphorylation
	bifurcation of SMO activity in HH response, with a DLG5-independent arm for suppression of GLI repressor formation and a second arm involving SMO interaction with DLG5 for GLI activation
	activated NOTCH1 leads to pronounced accumulation of SMO within primary cilia and elevated levels of full-length GLI3
	DYRK1B is a critical positive regulator of HH/GLI signaling downstream of SMO
	PTCH1/PTCH2 mediate likely secretion of a SMO-inhibitory cholesterol precursor
	SUMO pathway promotes HH signaling by regulating SMO subcellular localization , suggesting on how sumoylation regulates membrane protein trafficking
	. HH reciprocally controls trafficking of SMO and PTC through the SMURF family of E3 ubiquitin ligases
	HERC4, which binds to SMO, and regulates HH signalling by controlling SMO ubiquitination and degradation
	HERC4 acts as a tumor suppressor via destabilizing the oncoprotein SMO
	inactivation of PTCH1 by HH likely allows a transmembrane sterol to access this seven-transmembrane site (potentially through a hydrophobic tunnel), which drives the activation of SMO

cell & other

REGULATION

activated by

after loss of PTCH1 function

Other	targetting numerous genes, HOX, BMP
	multi-monoubiquitinated and its ubiquitination is inhibited by HH and by phosphorylation

ASSOCIATED DISORDERS

corresponding disease(s)

CJS , PHLS

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral somatic mutation       in basal cell carcinoma (BCC) of the skin tumoral       gain of function by somatic mutation in sporadic nevoid basal cell carcinoma syndrome (NBCCS) and primitive neuroectodermal tumors genes (HOX,BMP..) tumoral         loss of SMO impairs haematopoietic stem cell renewal and decreases induction of chronic myelogenous leukemia by the BCR-ABL1 oncoprotein tumoral     --other   constitutively active SMO augments CML stem cells and accelerate disease tumoral somatic mutation       in meningiomas tumoral     --over   is a mechanism for the activation of Hedgehog signaling in human pancreatic cancer-associated stromal fibroblasts tumoral     --low   by promoter methylation in colorectal cancer patients constitutional germinal mutation       in a patient with both anterior segment dysgenesis (congenital corneal opacity, cataract) and morning glory syndrome

Susceptibility

Variant & Polymorphism

Candidate gene
Marker
Therapy target
	System Type Disorder Pubmed cancer digestive pancreas stromal cells may be a therapeutic target for SMO antagonists in pancreatic cancer cancer brain   acquired mutations in SMO can serve as a mechanism of drug resistance in human cancer (in medulloblastoma) cancer bone   inactivation of SMO may be a useful approach to the treatment of patients with osteosarcoma

ANIMAL & CELL MODELS

Smo-/-mutant have developmental defects with failure to turn,arresting at stages with a small heart tube,an open gut and cyclopia