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FLASH GENE

Symbol

TYROBP

contributors: mct/npt - updated : 03-05-2016

HGNC name	TYRO protein tyrosine kinase binding protein
HGNC id	12449

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Corresponding disease	PLOSL1 polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 1
Location	19q13.12      Physical location : 36.395.305 - 36.399.211
Synonym name	DNAX-activating protein
	killer activating receptor associated protein
	DNAX-activation protein 12
	KAR-associated protein
Synonym symbol(s)	DAP12, KARAP, PLO-SL, PLOSL,

DNA

TYPE	functioning gene
STRUCTURE	3.91 kb     5 Exon(s)

10 Kb 5' upstream gene genomic sequence study

motif	repetitive sequence   ALU
text structure	Alu sequences in 5' utr and intron 4

MAPPING

cloned

Y

linked

status

confirmed

Map	cen - D19S425 - GPI - TYROBP - COX6B1 - D19S208 - CAPNS1 ,D19S224 - qter
Authors	GeneMap (98)

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_003332 5 - 608 NP_003323 12.18 113 - 2013 23715743 NM_198125 5 - 605 NP_937758 12.1 112 - 2013 23715743 NM_001173515 4 - 572 NP_001166986 - 101 - 2013 23715743 NM_001173514 3 - 575 NP_001166985 11.04 102 - 2013 23715743

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 Digestive mouth tongue     predominantly Hearing/Equilibrium ear       highly Nervous brain         Homo sapiens Reproductive female system breast mammary gland

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol   bone marrow     highly Connective adipose     highly

cells

System Cell Pubmed Species Stage Rna symbol Blood/Hematopoietic leukocyte Blood/Hematopoietic monocyte Lymphoid/Immune macrophage Nervous glia Homo sapiens Nervous neuron

cell lineage

cell lines

fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	a signal sequence
	a short extracellular domain
	a transmembrane domain
	a cytoplasmic tail with the immunoreceptor tyrosine based activation motif (ITAM)

mono polymer

homomer , dimer

HOMOLOGY

Homologene

FAMILY	CD3 zeta family
	TYROBP family

CATEGORY

adaptor

SUBCELLULAR LOCALIZATION	plasma membrane
	intracellular
	intracellular,cytoplasm
text	type I transmembrane protein

basic FUNCTION	playing a role in signal transduction, bone modeling, brain myelination, and inflammation
	general macrophage fusion regulator, involved in modulating the expression of several macrophage-associated genes, including those encoding known mediators of macrophage fusion, such as DCST1 and DCST2 and Cadherin 1
	involved in programming of macrophages through the regulation of gene and protein expression to induce a fusion-competent state
	HCST and TYROBP, can either activate or inhibit immune responses
	trans-membrane adaptor molecule that transduces activating signals in NK and myeloid cells
	CLEC5A associates with its adaptor protein TYROBP to activate a signaling cascade resulting in activation of downstream kinases in inflammatory responses
	ITAM molecules, FCER1G, TREM2 and TYROBP play an important role in osteoclast development and activity
	impacts trafficking and surface stability of killer immunoglobulin-like receptors on natural killer cells
	is an immunoreceptor tyrosine-based activation motif (ITAM)-containing adaptor protein found in myeloid cells and natural killer cells
	TREM2 and its signaling adaptor protein TYROBP/DAP12 play important roles in signal transduction in dendritic cells, osteoclasts, tissue macrophages, and microglia
	role for TYROBP expression in tissue-resident alveolar macrophages in mediating acute noninfectious tissue injury through regulation of neutrophil trafficking
	role of TYROBP in stabilizing TREM2-C-terminal fragment, thereby protecting against excessive pro-inflammatory responses
	significant role in the initial inflammatory response, bone remodeling and regeneration
	is an immunoadaptor protein with associated immunoreceptors on myeloid lineage cells, including osteoclasts
	TREM2 and TYROBP—possess the ability to modulate critical cellular functions via crosstalk with diverse signaling pathways

CELLULAR PROCESS

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

SIGLEC15-TYROBP-SYK-signaling cascade plays a critical role in functional osteoclast formation

a component

a disulfide-bonded dimer

INTERACTION

DNA

RNA

small molecule

protein	associate with the killer-cell inhibitory receptor (KIR) family of membrane glycoproteins
	interacting with SIRPB1 and TREM1
	interacts with CLECSF5
	PLXNA1 associates with the triggering receptor expressed on myeloid cells-2 (TREM2), linking semaphorin-signalling to the immuno-receptor tyrosine-based activation motif (ITAM)-bearing adaptor protein, TYROBP
	TYROBP and TREM2, with SYK are required for the cytokine-induced formation of giant cells
	CLEC5A associates with both TYROBP and HCST in osteoclasts and bone marrow-derived macrophages, where HCST association depends almost entirely on TYROBP
	interaction with HCST, a signaling adaptor molecule that play a key role in the TREM2- and TYROBP-dependent recruitment of PI3K to the signaling complex
	TREM1 associated with TYROBP in hypoxic mature dendritic cells, and its engagement elicited TYROBP-linked signaling, resulting in MAPK3, AKT1, and NFKBIA phosphorylation
	binding of dengue virus to CLEC5A triggers signaling through the associated adapter molecule TYROBP, stimulating proinflammatory cytokine release
	SIGLEC15 is a TYROBP-associated receptor in osteoclasts
	OSCAR and TREM2 are essential receptors that pair with adaptor molecules Fc receptor common gamma chain (FCR1G) and TYROBP respectively to induce calcium signalling
	TYROBP/TREM2 activation plays an important role in activation and differentiation of osteoclasts, brain and bone homeostasis and inhibition of the toll-like receptor (TLR) signaling in macrophages and dendritic cells
	SIGLEC15 interacts with the adapter protein TYROBP and can induce AKT1 activation when clustered on the osteoclast cell surface, which likely represents its normal signaling function
	capable of associating with KLRD1 and TYROBP but the complex was retained intracellularly at the endoplasmic reticulum instead of being expressed on cell surfaces, and this localization was dependent on a sequence of hydrophobic AAs in the extracellular domain of KLRC3
	immunoreceptor that regulates osteoclast development and bone resorption in association with an immunoreceptor tyrosine-based activation motif (ITAM) adaptor protein (TYROBP)
	TREM2 is a TYROBP-associated receptor expressed in microglia, macrophages, and other myeloid-derived cells

cell & other	associating with natural killer cell receptors lacking ITIM sequence (see KIRDS1 to 5), resulting in cellular activation
	associating with KLRD1, KLRC2, CLECSF5

REGULATION

ASSOCIATED DISORDERS

corresponding disease(s)

PLOSL1

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional       loss of function impairs fracture healing constitutional     --over   results in both increased osteoclastogenesis and impaired hematopoiesis underlining the relationship between bone homeostasis and hematopoiesis

Susceptibility

Variant & Polymorphism

Candidate gene
Marker
Therapy target
	System Type Disorder Pubmed cancer hemopathy   inhibitors of HCST and TYROBP or other proteins involved in this signaling pathway will be attractive therapeutic targets for the treatment of large granular lymphocyte (LGL) leukemia immunology autoimmune   inhibitors of HCST and TYROBP or other proteins involved in this signaling pathway will be attractive therapeutic targets for the treatment of autoimmune diseases and syndromes

ANIMAL & CELL MODELS

Dap12-deficient mice exhibit mild osteopetrosis