RGD Reference Report - Overexpression of the autoimmunity-associated phosphatase PTPN22 promotes survival of antigen-stimulated CLL cells by selectively activating AKT. - Rat Genome Database

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Overexpression of the autoimmunity-associated phosphatase PTPN22 promotes survival of antigen-stimulated CLL cells by selectively activating AKT.

Authors: Negro, R  Gobessi, S  Longo, PG  He, Y  Zhang, ZY  Laurenti, L  Efremov, DG 
Citation: Negro R, etal., Blood. 2012 Jun 28;119(26):6278-87. doi: 10.1182/blood-2012-01-403162. Epub 2012 May 8.
RGD ID: 11535006
Pubmed: PMID:22569400   (View Abstract at PubMed)
PMCID: PMC3383194   (View Article at PubMed Central)
DOI: DOI:10.1182/blood-2012-01-403162   (Journal Full-text)

A polymorphic variant of the phosphatase PTPN22 has been associated with increased risk for multiple autoimmune diseases. The risk allele is thought to function by diminishing antigen-receptor signals responsible for negative selection of autoreactive lymphocytes. We now show that PTPN22 is markedly overexpressed in chronic lymphocytic leukemia (CLL), a common malignancy of autoreactive B lymphocytes. We also show that overexpression of PTPN22 significantly inhibits antigen-induced apoptosis of primary CLL cells by blocking B-cell receptor (BCR) signaling pathways that negatively regulate lymphocyte survival. More importantly, we show that PTPN22 positively regulates the antiapoptotic AKT kinase, which provides a powerful survival signal to antigen-stimulated CLL cells. This selective uncoupling of AKT from other downstream BCR signaling pathways is a result of inhibition of a negative regulatory circuit involving LYN, CD22, and SHIP. Finally, we show that PTPN22 can be effectively down-regulated by the PKC inhibitors ruboxistaurin and sotrastaurin, resulting in enhanced killing of CLL cells exposed to proapoptotic BCR stimuli. Collectively, these data suggest that PTPN22 overexpression represents a protective mechanism that allows autoantigen-activated CLL cells to escape from negative selection and indicate that this mechanism could be exploited for therapeutic purposes by targeting PTPN22 with PKC inhibitors.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
chronic lymphocytic leukemia  IEP 11535006protein:increased expression:B cell (human)RGD 
chronic lymphocytic leukemia  ISOPTPN22 (Homo sapiens)11535006; 11535006protein:increased expression:B cell (human)RGD 

Objects Annotated

Genes (Rattus norvegicus)
Ptpn22  (protein tyrosine phosphatase, non-receptor type 22)

Genes (Mus musculus)
Ptpn22  (protein tyrosine phosphatase, non-receptor type 22 (lymphoid))

Genes (Homo sapiens)
PTPN22  (protein tyrosine phosphatase non-receptor type 22)


Additional Information