Pulling strings below the surface: hormone receptor signaling through inhibition of protein tyrosine phosphatases.
Hormones, cytokines, and related proteins (such as soluble hormone receptors) play an important role as therapeutic agents. Most hormone receptors signal through a mechanism that involves phosphorylation of the receptor's tyrosine residues. At any given moment, the receptor's phosphorylation state depends on the balance of kinase and phosphatase activities. Recent findings point to the exciting possibility that receptor signaling can be regulated by inhibition of protein tyrosine phosphatases (PTPs) that specifically hydrolyze receptor tyrosine-phosphates, or their immediate downstream effectors. This strategy has now been firmly validated for the insulin receptor and PTP1B; inhibiting PTP1B activity results in stimulation of the insulin receptor and signaling, even in the absence of insulin. This and similar findings suggest that PTP inhibitors have potential as hormone mimetics. In the present review, we outline this new paradigm for therapeutic regulation of the insulin receptor and discuss evidence that hints at other specific receptor-PTP pairs.
Espanel
X
X
Serono Pharmaceutical Research Institute, Geneva, Switzerland.
Wälchli
S
S
Gobert
R P
RP
El Alama
M
M
Curchod
M L
ML
Gullu-Isler
N
N
Hooft van Huijsduijnen
R
R
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors; D011972:Receptor, Insulin / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism*; D054411:Receptors, Leptin; D011986:Receptors, Somatotropin / Q000378:metabolism; D015398:Signal Transduction
D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D011986:Receptors, Somatotropin; D019000:Phosphotyrosine; D011972:Receptor, Insulin; D017027:Protein Tyrosine Phosphatases