PAG1

Official Full Name

phosphoprotein membrane anchor with glycosphingolipid microdomains 1

Organism

Homo sapiens

GeneID

55824

Background

The protein encoded by this gene is a type III transmembrane adaptor protein that binds to the tyrosine kinase csk protein. It is thought to be involved in the regulation of T cell activation. [provided by RefSeq, Jul 2008]

Synonyms

CBP; PAG;

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Detailed Information

PAG1 hindered allergen-induced murine lung type 2 inflammation

Phosphoprotein associated with glycosphingolipid-enriched microdomains1 (PAG1) has shown with impact on immune receptor signaling in T and B cells as a transmembrane adaptor protein. Evidence from genome-wide association studies of asthma indicated that there is an association between the genetic variants responsible for the PAG1 expression regulation and asthma risk. However, whether the relatedness of PAG1 expression and asthma pathophysiology can be accounted by causality or not is still not fully understood. Lipid rafts resided transmembrane phosphotyrosylated adaptor protein is encoded by PAG1. Besides its dispensable role for T-cell development and function, negative regulation on T-cell immune responses of PAG1 has been reported. T-cell activation can be inhibited by PAG1 via protein tyrosine kinase CSK (C-terminal SRC kinase) upon T-cell receptor (TCR) stimulation. Loss of PAG1 can initiate T-cell hyper-activation and induction of a detrimental T-helper type1 (T_h1) response in the experimental autoimmune encephalomyelitis. But the effect of PAG1 expression on the development of T_h2 responses remains to be elusive. In contrast to SRC kinase Lyn inhibition followed by B-cell receptor signaling and B-cell activation, PAG1 works as a feedback-loop inhibitor in mast cells, where SRC kinase hyperphosphorylate PAG1. And increased recruitment of CSK to lipid rafts which in turn inactivates SRC kinases can be delivered to down-regulate mast cell activation and degranulation by the PAG1.

PAG1 acts as a novel tumor suppressor in neuroblastoma

As the most common extracranial pediatric solid tumor, neuroblastoma has high mortality rates and association with tyrosine kinase c-Src, which is playing an important role in differentiation of NB cells. PAG1 (Cbp, Csk binding protein) was characterized as a central inhibitor of c-Src and other Src family kinases to function as a novel tumor suppressor in NB. Proliferation and anchorage-independent colony formation with increased activation of AKT and ERK downstream of c-Src can be promoted by PAG1 knockdown in NB cells, and these effects can be counteracted by PAG1 over-expression. In orthotopic xenograft model, NB tumorigenicity can be significantly inhibited by PAG1 over-expression. All those conditioned that reactivation of PAG1 and inhibition of c-Src kinase activity role as a novel therapeutic approach for high-risk NB.

Figure 1. PAG1 protein works as a transmembrane adaptor protein in the lipid raft signaling cluster for regulation of Src family kinase (SFKs), which is a convergent point for multiple pathways regulating N-methyl-D-aspartate (NMDA) receptors. (Fangkun Jing, et al. 2020)

References:

Ullah M A, Vicente C T, Collinson N, et al. PAG1 limits allergen‐induced type 2 inflammation in the murine lung. Allergy, 2020, 75(2): 336-345.
Agarwal S, Ghosh R, Chen Z, et al. Transmembrane adaptor protein PAG1 is a novel tumor suppressor in neuroblastoma. Oncotarget, 2016, 7(17): 24018.
Balan S, Iwayama Y, Yamada K, et al. Sequencing and expression analyses of the synaptic lipid raft adapter gene PAG1 in schizophrenia. Journal of Neural Transmission, 2015, 122(3): 477-485.

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