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FLASH GENE

Symbol

AMOT

contributors: mct/pgu - updated : 12-04-2016

HGNC name	angiomotin
HGNC id	17810

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

DNA

TYPE	functioning gene
STRUCTURE	65.94 kb     12 Exon(s)

10 Kb 5' upstream gene genomic sequence study

MAPPING

cloned

Y

linked

N

status

confirmed

RNA

TRANSCRIPTS	type	messenger

text	not completely determined alternatively spliced transcript variants encoding different isoforms have been described (PMID: 16043488)

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_133265 12 - 6514 NP_573572 72 675 expressed during the migratory phase of retinal angiogenesis 2009 19565639 variant 1 - p80 promotes angiogenesis, in part, by conferring a hypermigratory phenotype to endothelial cells AMOTL1 associates with this p80-angiomotin-containing complex via its coiled-coil domain is a novel component of the CDH11 complex and Amot-p80 is critical for CDH11-mediated cell migration NM_001113490 11 - 6945 NP_001106962 130 1084 expressed during the period of blood vessel stabilization and maturation in retinal angiogenesis 2013 23564455 be coprecipitated with MAGI-1b variant 2 - p130 N-terminal domain of p130 serves as a targeting domain responsible for localization of p130-AMOT to actin and tight junctions ubiquitinated at lysine 481 by ITCH, resulting in increased AMOT130 stability significant consequence of AMOT130 binding to ITCH is the induction of its ligase activity for self and substrate ubiquitination recruits the E3 protein-ubiquitin ligase atrophin-1 interacting protein 4 (ITCH), that binds and ubiquitinates AMOT130, resulting in a reduction in AMOT130 residence at actin fibers and a significant enhancement of the stability of AMOT130 protein phosphorylation by LATS1/2 is found to be a key feature that enables it to inhibit YAP1-dependent signaling and cell growth

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   vessel capillary     highly Homo sapiens Digestive mouth tongue     predominantly Endocrine neuroendocrine pituitary     moderately Lymphoid/Immune spleen       highly Nervous brain basal nuclei         spinal cord         Reproductive female system placenta     moderately Urinary kidney       moderately

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Epithelial barrier/lining       Lymphoid         Muscular       moderately Nervous central

cells

System Cell Pubmed Species Stage Rna symbol Cardiovascular endothelial cell Homo sapiens

cell lineage

cell lines

fluid/secretion

at STAGE

physiological period

pregnancy

Text	placenta (large vessels)

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	a PPXY motif in the N terminus of AMOT necessary for its interactions , and N-terminal regions contain a conserved HXRXXS consensus site for LATS1/2-mediated phosphorylation
	a coiled-coil domain
	a lipid binding domain that bind with high affinity to membranes containing monophosphorylated phosphatidylinositols and cholesterol
	a consensus motif for binding to PDZ domain at the C terminus, C-terminal PDZ-binding motifs, required for the interactions with AMOTL1, AMOTL2, MPDZ, and INADL

HOMOLOGY

Homologene

FAMILY

angiomotin family, Amot/JEAP family

CATEGORY

regulatory

SUBCELLULAR LOCALIZATION	plasma membrane,junction,tight
	intracellular
	intracellular,cytoplasm,organelle,endosome
	intracellular,cytoplasm,cytosolic,vesicle
	intracellular,cytoplasm,cytoskeleton
text	located to the leading edge of migrating endothelial cells
	actin filament
	lamellipodium
	apparent at TJs as well as apical membranes, and mostly co-localized with MPDZ
	targeted along with associated apical polarity proteins to the endocytic recycling compartment via its membrane binding domain

basic FUNCTION	mediating angiostatin inhibition of migration and tube formation of endothelial cells
	stimulating cell motility
	playing a role in the assembly of endothelial cell-cell junctions
	maintaining tight junctions integrity by the coordinate regulation of Cdc42 and by linking specific components of the TJ to intracellular protein trafficking, when binding to ARHGAP17
	important role in growth factor-induced migration of endothelial cells
	AMOT appears to control the polarity of vascular tip cells whereas AMOTL1 mainly affects the stability of cell-cell junctions of the stalk cells
	associates with cell junctions and binds apical polarity proteins, which underlie its ability to control cell shape and migration
	may coordinate the dysregulation of cell polarity with the induction of neoplastic growth in mammary cells
	functions downstream of Merlin and upstream of ARHGAP17, a small GTPase Activating Protein, as a positive regulator of RAC1
	activate LATS2 through a novel conserved domain that binds and activates LATS2
	membrane-associated protein that is expressed in ECs (endothelial cells) and controls migration, TJ (tight junction) formation, cell polarity and angiogenesis
	AMOT, AMOTL1 and AMOTL2, play critical roles in the Hippo pathway by regulating the subcellular localization of the co-activators YAP1 and TAZ
	is crucial for the maintenance of nuclear YAP1 to promote renal epithelial and Renal cell carcinoma (RCC) proliferation
	multifunctional protein involved in endothelial cell migration and tube formation and angiogenesis
	MAMDC4 and AMOT have a greater association in subconfluent cells compared with confluent cells, and this association is regulated at the endosomal membrane
	EDIL3, AMOT and ECM1 are involved in the excessive angiogenesis and vasodilation observed in psoriasis

CELLULAR PROCESS	cell organization/biogenesis
	cell communication

PHYSIOLOGICAL PROCESS

development

text	actin cytoskeleton organization and biogenesis
	positive regulation of angiogenesis
	positive regulation of blood vessel endothelial cell migration

PATHWAY

metabolism

signaling

	tankyrase-RNF146-AMOT axis is an upstream pathway regulating YAP1
	Hippo pathway negatively regulates the actin-binding activity of AMOT family members through direct phosphorylation

a component

forms a ternary complex together with INADL (or its paralogue MPDZ) and PLEKHG5, involved in directional migration of capillaries in the embryo

INTERACTION

DNA

RNA

small molecule

protein	angiostatin
	ARHGAP17 via its coiled-coil domain
	interacting with MPDZ and INADL (interaction not necessarily responsible for their proper subcellular distribution
	directly binds the scaffolding proteins INADL and MPDZ and redistributes them and their binding partners from the plasma membrane to endosomes
	AMOT, AMOTL1 and AMOTL2, are YAP1-associated proteins
	AMOT and AMOTL1 interact with YAP1 via the first WW domain of YAP1
	interacting with YAP1 and TAZ (YAP1 and TAZ inhibition by AMOT-mediated tight junction localization)
	functions downstream of NF2 and upstream of ARHGAP17, a small GTPase Activating Protein, as a positive regulator of RAC1
	MCAM binds to angiomotin to stimulate a proangiogenic response
	ITCH bind and ubiquitinate AMOT at residue Lys-481
	promotes the ubiquitination of YAP1 by ITCH and prevents ITCH from binding to large tumor suppressor 1
	acts as a YAP1 cofactor, preventing YAP1 phosphorylation and augmenting its activity toward a specific set of genes that facilitate tumorigenesis
	AMOT is a direct substrate of LATS1/LATS2 mediating functions of the Hippo pathway in endothelial cell migration and angiogenesis
	LATS1, LATS2 can synergize with F-actin perturbations by phosphorylating free AMOT130 to keep it from associating with F-actin
	MAMDC4 interacts with both AMOT and occludin and preferentially associates with occludin in confluent cells but with AMOT family members in subconfluent cells
	MAMDC4 competes with YAP1 for binding to AMOT proteins in subconfluent cells
	AMOT can interact with YAP1 to either stimulate or inhibit YAP1 activity, playing a potential role in cell proliferation

cell & other

REGULATION

ASSOCIATED DISORDERS

corresponding disease(s)

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral     --over   in breast cancer tissues and was important in the promotion of breast cancer cell proliferation and invasion

Susceptibility

Variant & Polymorphism

Candidate gene
Marker
Therapy target
	System Type Disorder Pubmed miscelleaneous vascular   using angiomotin antibodies for specifically targeting endothelial migration in angiogenesis-dependent diseases

ANIMAL & CELL MODELS