SLP-76 LCP2, pp76
Molecule TypeAntigen ExpressionMolecular Weight
Min / Max
Non-lineage Restricted Molecule
Unknown
Thymocyte, Immature
T Cell, Mature
Platelet
Macrophage
NK Cell
Megakaryocyte
Mast Cell
75 / 80

Expression
SLP-76 is a cytosolic adaptor protein expressed on several cell types of hematopoietic origin.  SLP-76 associates with other molecules and is required for coupling receptor ligation with more distal signaling events on immature thymocytes, mature T cells, platelets, mast cells, macrophages, NK cells, and megakaryocytes.  SLP-76 is not expressed on murine B cells.  Expression is regulated during thymocyte development.  The expression increases following activation on mature T cells and remains elevated on the memory cell subset.

Structure
MOLECULAR FAMILY NAME: slp-76 family -->adaptor proteins.

SLP-76 names: SH2 domain-containing leukocyte protein of 76kD (spl-76), lymphocyte cytosolic protein 2 (LCP2), 76-kDa phosphoprotein (pp76), and 76-kDa Vav-associated protein.

SLP-76 was originally identified as a substrate of the ZAP-70 protein tyrosine kinase following TCR ligation in the leukemic T cell line Jurkat.  Human and murine SLP-76 cDNAs encode 533 aa proteins that are 72% identical and are comprised of  3 major modular domains that regulate protein interactions.  The NH2-terminus contains an acidic- domain that harbors several tyrosine-residues that are phosphorylated following TCR ligation.  The acidic-region also contains 1 PEST domain.  The central portion of SLP-76 is rich in proline-residues.  There is 1 SH2 domain present at the COOH-terminus of the molecule.

MOLECULAR MASS
Cell Type Unreduced Reduced
Lymphocytes 76 kDa 76 kDa

POST-TRANSCRIPTIONAL MODIFICATION

No evidence for alternative splicing has been obtained.  Message stability has not been studied. While the human SLP-76 transcripts contain a relatively short 3' UTR, the murine transcript contains a relatively long 3' UTR with several potential AU-rich elements.

POST-TRANSLATIONAL MODIFICATION

Tyrosine residues at positions 113 and 128 are the predominant sites of phosphorylation following TCR ligation.  The tyrosine at position 145 may also be a candidate for phosphorylation.  There is also evidence for constitutive serine phosphorylation in the acidic domain, although the exact serine residues involved have not been mapped.



Ligands
LIGANDS AND MOLECULES ASSOCIATED WITH SLP-76
Molecule Comment
Vav Vav SH2 domain associates with SLP-76 phosphotyrosines 113 and/or 128
Nck Nck SH2 domain associates with SLP-76 phosphotyrosines 113 and/or 128
Gads Gads SH3 domains associate with SLP-76 proline rich domain, 224 aa-244 aa.
SLAP-130/Fyb Phosphotyrosine dependent association with SLP-76 SH2 domain
Grb2 Grb2 SH3 domains associate with SLP-76 proline rich domain, 224 aa-244 aa.  This association has only been demonstrated in vitro.
Itk Itk SH2 domain associates with tyrosine phosphorylated SLP-76.
PLCg1 PLCg1 SH2 domain associates with tyrosine phosphorylated SLP-76
p56lck SH3 domain of Lck associates with proline-rich region of SLP-76


Function
SLP-76 functions to promote proliferation, differentiation and allelic exclusion in immature thymocytes following pre-TCR ligation and activation of mature T cells following ligation of the TCR.  SLP-76 is required to couple the collagen receptor(s) expressed on platelets with more distal signaling events leading to aggregation and granule release.  SLP-76 connects high affinity IgE receptor, Fce RI to downstream effectors responsible for degranulation and cytokine production in mast cells.  A number of SLP-76 associated molecules have been identified, however it is not clear how SLP-76 and any associated proteins function to regulate the processes outlined above.  Using SLP-76 deficient T cell lines or mice have provided strong evidence that SLP-76 plays a positive role in promoting T cell development and activation as well as mast cell and platelet function.

BIOCHEMICAL ACTIVITY

SLP-76 has no enzymatic activity and appears to function primarily as an adaptor or scaffold protein.

DISEASE RELEVANCE AND FUNCTION OF SLP-76 IN INTACT ANIMAL

To date, no SLP-76 related human disease or pathology has been reported.  Mice made deficient for SLP-76 by targeted disruption of the SLP-76 genomic locus manifest a complete block in thymocyte development at an early stage of maturation.  SLP-76 deficient mice also exhibit a diffuse bleeding diathesis and selectively perish at or shortly after birth.  SLP-76 deficient mice are resistant to IgE mediated anaphylaxis.  SLP-76 deficient platelets fail to respond to collagen and fibrinogen while maintaining responsiveness to thrombin.  The relationship between collagen dependent platelet dysfunction and bleeding has not been established.


Comments
SLP-76 has been implicated in the regulation of actin polymerization and cytoskeletal changes associated with TCR ligation.  Overexpression of SLP-76 in a T cell line potentiates Erk phosphorylation and activation as well as transcriptional activation of AP-1 and NF-AT.  SLP-76 expression is required to promote tyrosine phosphorylation of PLCg1 in T cells and in mast cells and PLCg2 platelets.

MOLECULAR INTERACTIONS -
PROTEINS AND DNA ELEMENTS WHICH REGULATE TRANSCRIPTION OF SLP-76: No information.

SUBSTRATES

SLP-76 is not an enzyme, and therefore does not have any substrates in the enzymatic sense.

ENZYMES WHICH MODIFY SLP-76
Enzyme Comment
ZAP-70 The Syk tyrosine kinase ZAP-70 has been demonstrated to phosphorylate SLP-76 tyrosine residues 113 and/or 128 following activation.
Syk It is likely that SLP-76 is also a substrate of Syk in additional cell types, including platelets.

ADDITIONAL INSIGHTS

SLP-76 is a member of the growing family of adaptor proteins that have been found to be critical signaling intermediates in many cell types.  SLP-76 and adaptor proteins in general function to direct the assembly of macro-molecular signaling complexes which are in response to receptor ligation.  Adaptor proteins are capable of effectively propagating signals that emanate from receptor and non-receptor tyrosine kinases and disseminating these signals into various biochemical pathways.


Database accession numbers
AnimalPIRSWISSPROTEMGBL/GENBANK
 
Antibodies

Revised June 25, 2008


Contact us: Webmaster |  509-335-9515 | Accessibility | Copyright | Policies
College of Veterinary Medicine Washington State University, Pullman, WA, 99164-7010 USA
Copyright 1995-2003 Washington State University