Protein tyrosine phosphatase non-receptor type 11 (SHP2) (SHP2)

Protein tyrosine phosphatase non-receptor type 11 (SHP2) is a cytoplasmic enzyme encoded by the PTPN11 gene that serves as a critical signaling hub in various cellular processes [3, 13]. It is ubiquitously expressed and plays a pivotal role in the RAS/MAPK, PI3K/AKT, and JAK/STAT signaling pathways, typically acting as a positive regulator of signal transduction downstream of receptor tyrosine kinases and cytokine receptors [4, 12]. While germline mutations in SHP2 cause developmental disorders such as Noonan and LEOPARD syndromes, the wild-type form is frequently co-opted in solid tumors to facilitate oncogenic signaling and mediate resistance to targeted therapies [1, 19]. Therapeutic targeting of wild-type SHP2 primarily utilizes allosteric inhibitors that stabilize the protein in its auto-inhibited, closed conformation, preventing its activation by upstream signals [7, 14]. These inhibitors are currently being evaluated in clinical trials, often in combination with KRAS or EGFR inhibitors, to overcome adaptive resistance and enhance anti-tumor efficacy [9, 15]. Additionally, SHP2 is involved in immune checkpoint signaling, making its inhibition a potential strategy for augmenting immunotherapy responses [5, 11].

Other names

PTPN11SHP-2BPTP3CFCNS1PTP2CSAP2SH-PTP2SH-PTP3

Allosteric inhibition by stabilizing the inactive, auto-inhibited closed conformation of the protein [7, 8, 14].