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FLASH GENE

Symbol

SH2D1A

contributors: mct/npt - updated : 16-02-2016

HGNC name	SH2 domain protein 1A, Duncan's disease (lymphoproliferative syndrome)
HGNC id	10820

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

DNA

TYPE	functioning gene
STRUCTURE	26.86 kb     4 Exon(s)

10 Kb 5' upstream gene genomic sequence study

MAPPING

cloned

Y

linked

Y

status

confirmed

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_002351 4 splicing 2518 14.2 128 - 2012 23165210 NM_001114937 4 splicing 2498 - 125 - 2012 23165210 variant 3 - splicing 470 6.4 58 - 2012 23165210 variant 4 - splicing 530 14 125 - 2012 23165210 variant 5 - splicing 460 8.4 76 - 2012 23165210 variant 6 - splicing 420 6.9 62 - 2012 23165210

EXPRESSION

Type	restricted

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 blood / hematopoietic spleen           thymus         Digestive liver         Respiratory lung

tissue

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

cells

System Cell Pubmed Species Stage Rna symbol Lymphoid/Immune lymphocyte Lymphoid/Immune natural killer Lymphoid/Immune T cell

cell lineage
cell lines	EBV transformed B cell lines
fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	small protein containing a 5 AA terminal sequence SH2 domain
	a single src-homology-2 domain
	a 25 AA C terminus tail, highly homologous to INPP5D, required fo its binding to ARHGEF6 and ARHGEF7

HOMOLOGY

interspecies	homolog to murine Sh2d1a
	homolog to C.elegans Y51H7BR.5

intraspecies

homolog to INPP5D

Homologene

FAMILY

CATEGORY

adaptor

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,cytoplasm,cytosolic

basic FUNCTION	putative regulator of the signal transduction pathways initiated by interactions between the SLAM molecules at the interface between T and B cells
	sustaining the immune response by blocking inhibitory signal A mediated by INPP5D
	compelling for binding of phosphotyrosine to FCgammaRIIB (FCGR2B)
	may be involved in regulation of B-cell differentiation via switching of SLAMF1-mediated signaling pathways
	required for the recruitment of ARHGEF6, ARHGEF7 to the SLAM-family receptors
	may serving as a negative regulator of TRK receptor activation and downstream signaling
	acting as an intracellular adaptor protein by recruiting the protein tyrosine kinase FYN to the cytoplasmic domains of some of these receptors, which results in the initiation of specific downstream signal transduction pathways
	may play an important role in balancing positive versus negative immune responses (Li 2008)
	intracellular adaptor molecule expressed in T cells, natural killer (NK) cells, and some B cells (Li 2008)
	playing a role in the development of innate-like T cell lineages including natural killer T cells and in the regulation of interactions between B cells and T cells that are required for germinal center formation and long-term humoral immunity (Schwartzberg 2009)
	playing a novel role in B cells and extends its function to inhibitory immunoreceptor signaling and calcium mobilization (Ostrakhovitch 2009)
	is pivotal for nearly all phases, but not for maintenance, of T cell-driven B cell humoral immunity
	regulate T cell proliferation through the MAP-kinase Erk (Li 2009)
	plays essential roles during invariant NKT cell cytotoxicity and lytic synapse formation
	plays an essential role in collagen-induced arthritis (CIA) because of FYN-independent and FYN-dependent effects on follicular T helper (TFH) cells and, possibly, other T cell types
	small cytosolic adaptor protein expressed in hematopoietic lineages whose main function is to regulate intracellular signaling pathways induced by the triggering of members of the SLAM receptor family
	plays an essential role in the immune system mediating the function of several members of the SLAM family (SLAMF) of receptors, whose expression is essential for T, NK, and B-cell responses
	is essential for the development of type II NKT cells, and is critical for regulating type II NKT cell responses

CELLULAR PROCESS

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

signal transduction

	lymphocyte-activation molecule
	SLAM-SH2D1A signaling pathway

a component

INTERACTION

DNA

RNA

small molecule

protein	SLAM (signaling lymphocytic activation molecule)/CD150
	binding to p62dok (DOK1) and activating NFkappaB
	2B4/CD244 interaction dependent of PI3K
	CD84
	CD229/LY-9
	associating with the PAK-interacting exchange factor (PIX), a guanine nucleotide exchange factor (GEF) specific for Rac/Cdc42 GTPases, and participating in T cell activation
	interacted with NTRK1, NTRK2, NTRK3 receptors
	associates with several other cell-surface receptors including 2B4 (CD244), Ly9 (CD229), CD84 and SLAMF6
	binding to the inhibitory immunoreceptor CD22 that regulates calcium mobilization in B cells (Ostrakhovitch 2009)
	interacting with NCK1 (NCK1 is a novel physiological partner for SH2D1A and a direct regulator of TCR signaling and T cell proliferation (Li 2009)
	is a target of TP53 in T cells
	directly and specifically interacts with the cytosolic tyrosine 686 of PECAM1
	SH2D1A facilitates recruitment and activation of LCK at SLAMF6 receptors during restimulation-induced cell death

cell & other

REGULATION

activated by

NFKB

ASSOCIATED DISORDERS

corresponding disease(s)

LYP

related resource

SH2D1Abase: Mutation registry for X-linked lymphoproliferative syndrome (XLP)

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional germinal mutation       in fatal mononucleoses constitutional     --low   associated with a major defect in humoral immunity, resulting from a lack of T cell help for B cells

Susceptibility

to systemic lupus erythematosus (SLE)

Variant & Polymorphism SNP	intronic SNP of SH2D1A is associated with SLE

Candidate gene

Marker

Therapy target

ANIMAL & CELL MODELS

	Sap deficient mice were protected from systemic lupus erythematosus (SLE)
	mice deficient in the adaptor protein SAP (Sh2d1a) have a major defect in humoral immunity