Adapters Proteins

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 Adapters Proteins Background

Adaptor proteins in signal transduction

Membrane receptors sample the extracellular environment. When activated by threshold levels of cognate ligands, receptors stimulate a signaling cascade that leads to precise biological responses. Signaling proteins contain catalytic and adaptor functions that typically reside in discrete, independently folded domains. Most adaptor domains display binding specificity for peptide motifs in other signaling proteins that transmit and codify the signals. For example, Src kinase has a canonical kinase fold as well as a Src homology 2 (SH2) domain that bind to specific phosphotyrosine residues on activated receptors, and a Src homology 3 (SH3) domain that binds to polyproline (Pro-X-X-Pro) motifs. SH2 and SH3 domains are found in many other proteins and function to recruit signaling proteins into complexes where catalytic efficiency is greatly enhanced.

The terms adaptors and scaffolds are used interchangeably in the literature for non-catalytic proteins that cross-link and promote the assembly of specific signaling complexes. Herein, we refer to these proteins as “adaptor proteins.” In mammals´╝îadaptor proteins include the growth factor receptor-bound protein 2 (Grb2)/ Grb2-related adapter protein (Grap)/ Grb2-related adaptor downstream of Shc (Gads), Grb7/10/14, SH2B/ adapter protein with pleckstrin homology (APS)/ lymphocyte adaptor protein (Lnk), SH2D1-4, Shc1-4, SHB/SHD/SHE/SHF, and the non-catalytic region of tyrosine kinase (Nck)1/2 gene families, among others.

Differential expression or posttranslational modifications of an adaptor can determine whether a pathway will function in a particular cell type. For example, the SH2-containing collagen-related (Shc), alternative splice variants can have different interaction and pathway output, depending on their levels of expression in various tissues. In addition, relocalization of adaptors to a specific cellular compartment in a timely fashion is often a requirement of signal transduction fidelity. For example, Shc1 very rapidly recruits proteins associated with acute stimulation of epidermal growth factor receptor (EGFR), such as Grb2-associated binding protein 1/2 (Gab1/2) and Grb2-son of sevenless homolog 1 (Sos1) complex which promotes exchange of Rat sarcoma oncogene (Ras)-bound GDP by GTP, while slowly recruits signaling proteins that mediate negative regulation of EGFR signaling, such as protein tyrosine phosphatase, non-receptor type 12 (PTPN12).

The Shc adaptor proteins were first identified by screening a human cDNA library for sequences complementary to the SH2 domain of the feline sarcoma oncogene (c-fes) tyrosine kinase. Following this initial screen, three sequence-related Shc-like transcripts and proteins were identified. The mammalian Shc gene family comprises four members: ShcA, B, C and D. In addition, alternative splicing of ShcA and ShcC transcripts results in multiple protein isoforms. While ShcA is expressed in almost all tissues, ShcB (Sck/Sli/Shc2) and ShcC (Rai/N-Shc/Shc3) are found predominantly in the brain and ShcD is expressed mainly in brain and muscle tissues.

All of the Shc adaptor proteins are structurally characterized by the unique modular arrangement of a phospho-tyrosine binding (PTB) domain, a collagen homology 1 (CH1) region followed by a SH2 domain. The PTB and SH2 domains independently bind motifs containing phosphorylated tyrosine residues. The domains are separated by the CH1 region which contains three consensus tyrosine residues that are phosphorylated by tyrosine kinases. The phosphotyrosine residues subsequently serve as recognition motifs for the SH2 domain of proximal signaling molecules including GRB2.


GRB2 family of adaptors

The GRB2 family of adaptor proteins consists of three members (GRB2, GADS, and GRAP). GRB2 is the best characterized, followed by GADS and the least studied member, GRAP. These proteins are composed of a central SH2 domain flanked by two SH3 domains. The amino acid sequence homology of the full proteins as well as the specific domains highlights the high degree of similarity between GRB2, GADS, and GRAP. The SH2 domain facilitates the recognition of specific phospho-tyrosyl sequences on intracellular ligands such as LAT, EGFR, FGFR, CD28 and BCR-Abl. In contrast, the SH3 domain allows binding and recruitment of multiple proline-rich ligands, such as the guanine nucleotide exchange factor (GEF) SOS1 and adaptor protein SLP-76, to active proximal signaling zones initiated by RTKs. Nonetheless, the complete inventory of SH3 or SH2 domain ligands that bind the GRB2 family of adaptors is yet to be fully determined. These proteins are essential for driving the assembly of various multiprotein signaling complexes by connecting SH2 and SH3 domain ligands together. Due to their role in core signaling pathways, dysregulated signaling complexes driven by GRB2 family members have been linked to oncogenesis, autoimmunity, diabetes, and cardiovascular disease.


Endocytic adaptors

Endocytic adaptor proteins vary greatly in size (-300-3000 amino acids) and structure, but possess similar properties. Most of the clathrin adaptor proteins contain regions that interact with some or all of four types of binding partners: lipids, cargo, clathrin and accessory proteins. Cooperation between these interactions is required for efficient recruitment of adaptors to the plasma membrane, and is crucial for progression of the internalization process. In recent years, many studies have focused on characterizing how endocytic adaptor proteins bind to the plasma membrane (lipids), select cargo, and recruit clathrin, and how these functions are coupled to promote deformation of the plasma membrane. The findings will be discussed here, beginning with the clathrin-binding motifs, followed by interactions with lipid, cargo and accessory proteins.