The
proline-,
glutamic acid-,
serine- and
threonine-rich (PEST) family of
protein tyrosine phosphatases (
PTPs) includes
proline-enriched
phosphatase (PEP)/lymphoid
tyrosine phosphatase (LYP),
PTP-PEST, and PTP-hematopoietic stem cell fraction (HSCF). PEP/LYP is a potent inhibitor of T-cell activation, principally by suppressing the activity of Src family
protein tyrosine kinases (PTKs). This function seems to be dependent, at least in part, on the ability of PEP to bind
C-terminal Src kinase (Csk), a PTK also involved in inactivating
Src kinases. Interestingly, a polymorphism of LYP in humans (R620W) is a significant risk factor for
autoimmune diseases including
type 1 diabetes,
rheumatoid arthritis, and lupus. The R620W mutation may be a 'gain-of-function' mutation. In non-hematopoietic cells,
PTP-PEST is a critical regulator of adhesion and migration. This effect correlates with the aptitude of
PTP-PEST to dephosphorylate
cytoskeletal proteins such as Cas, focal adhesion associated-
kinase (FAK), Pyk2, and PSTPIP. While not established, a similar function may also exist in immune cells. Additionally, overexpression studies provided an indication that
PTP-PEST may be a negative regulator of lymphocyte activation. Interestingly, mutations in a
PTP-PEST- and PTP-HSCF-interacting
protein, PSTPIP1, were identified in humans with
pyogenic sterile arthritis, pyoderma gangrenosum, and acne (
PAPA) syndrome and
familial recurrent arthritis, two autoinflammatory diseases. These mutations abrogate the ability of PSTPIP1 to bind
PTP-PEST and PTP-HSCF, suggesting that these two
PTPs may be negative regulators of
inflammation.