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FLASH GENE

Symbol

FERMT3

contributors: mct - updated : 12-09-2018

HGNC name	fermitin family homolog 3 (Drosophila)
HGNC id	23151

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	F0, F1, F2, and F3 subdomains with in addition a pleckstrin homology (PH)5 domain inserted in the F2 domain
	a pleckstrin homology PH domain having binding affinity for phosphoinositide, and having a major role in membrane association of FERMT3 that is enhanced by the binding of ITGB2 to ICAM1
	two plasma-membrane-binding ezrin/radixin/moesin domains
	lipid interactions of the 83-AAs F1 loop, with an isolated N-terminal peptide fragment, or EK21, containing a poly-Lys sequence motif, important for membrane interactions
	two C-terminal FERM domains, similar with that of talin, and this bipartite FERM (four point one protein, ezrin, radixin, moesin) domain is interrupted by a pleckstrin homology domain

HOMOLOGY

intraspecies

homolog to FERMT1, FERMT2

Homologene

FAMILY

kindlin family

CATEGORY

chaperone/stress , regulatory

SUBCELLULAR LOCALIZATION	extracellular
	plasma membrane,junction
	intracellular
	intracellular,cytoplasm,organelle,membrane
	intracellular,cytoplasm,cytoskeleton
text	associated with the B cell membrane but is then further recruited in a PH-dependent manner following an adhesion event

basic FUNCTION	essential element for platelet integrin activation in hemostasis and thrombosis
	focal adhesion proteins, acting as a transcriptional repressor in NF-kappaB signaling pathway
	regulating cell apoptotic pathway
	cytoplasmic component of cell-ECM adhesions that bind to beta-integrin cytoplasmic tails directly and cooperate with talin in integrin activation
	essential role for integrin signalling and cell-ECM adhesion regulation
	is more critical to ITGB2 than to ITGB1-adhesive functions in human lymphocytes
	focal adhesion proteins implicated in integrin activation
	essential to activate the ITGB1, ITGB2, ITGB3
	plays a role in integrin-mediated adhesion of endothelial cells
	required to activate leukocyte and platelet integrins
	FERMT3-mediated signaling from multiple integrin classes is required for osteoclast-mediated bone resorption
	selectively contributes to a final TCR-triggered outside-in stabilization of bonds generated between chemokine-primed ITGB2 molecules and cell-surface ICAM1
	is also required for integrin outside-in signaling, and it may interact with cytoplasmic protein(s) that modulate cell spreading
	plays a role in integrin alphaLbeta2 outside-in signaling, and it can induce integrin alphaLbeta2 micro-clustering
	critical for hemostasis, immunity, and bone metabolism via its role in integrin activation
	critical role in integrin activation and focal adhesion assembly
	main activator and binding partner of integrins in hematopoietic cells, that can be cleaved by calpain in an activation-dependent manner
	integrin-binding focal adhesion adaptor absent in patients with leukocyte and platelet adhesion deficiency syndrome and critical for firm integrin-dependent leukocyte adhesion
	FERMT3-stabilized integrin adhesions, although essential for lymphocyte arrest on blood vessels and interstitial motility, are not obligatory for leukocyte diapedesis
	promotes firm adhesion of T cells to primary brain microvascular endothelial cells
	regulates integrin activation and adhesion reinforcement of effector T cells
	major regulator of integrin function in hematopoietic cells
	influences breast cancer progression by influencing the crosstalk between ITGB1 and TWIST to increase VEGFA production

CELLULAR PROCESS	cell life, cell death/apoptosis
	nucleotide, transcription, regulation

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

a component

forms a ternary complex with the Talin and ITGB1 cytoplasmic tails

INTERACTION

DNA

RNA

small molecule

protein	interact with integrin beta tails
	interact with many components of cell–ECM adhesions-such as migfilin and integrin-linked kinase-to promote cytoskeletal reorganization
	key lymphocyte function-associated antigen-1 (ITGB2) coactivator
	interacts with the receptor for activated-C kinase 1 (GNB2L1), a scaffold protein that folds into a seven-blade propeller
	enriched within focal clusters of high-affinity ITGB2, which promoted physical linkage with ORAI1
	binds PI(3,4,5)P3 through the PH domain and contributes to the association of FERMT3 with the B cell membrane
	binding of ITGB2 to ICAM1 has a downstream effect in the recruitment of kindlin 3 to the membrane that is PH-dependent
	role of FERMT3 phosphorylation in ITGB3 activation, providing a basis for functional differences between FERMT3 and the two other kindlin paralogs
	FERMT3-mediated integrin adhesion is dispensable for quiescent but essential for activated hematopoietic stem cells
	interacts with the ribosome and regulates MYC expression required for proliferation of chronic myeloid leukemia cells

cell & other

REGULATION

ASSOCIATED DISORDERS

corresponding disease(s)

LAD3

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional     --low   results in severe bleeding and resistance to arterial thrombosis constitutional         resulting in postnatal lethality

Susceptibility

Variant & Polymorphism

Candidate gene

Marker

Therapy target

ANIMAL & CELL MODELS

	kindlin-3-deficient mice develop severe osteopetrosis because of profound adhesion and spreading defects in bone-resorbing osteoclasts
	mice lacking Kindlin-3 in T cells were immunized with an autoantigen to induce experimental autoimmune encephalitis (EAE), a model of multiple sclerosis, and autoreactive Kindlin-3–null T cells extravasate only when the brain microvasculature expresses high integrin ligand levels
	kindlin-3-null mice, which die perinatally of severe bleeding and leukocyte adhesion deficiency, mice expressing as little as 5p100 of kindlin-3 were viable and protected from spontaneous bleeding and infections