Acts downstream of various receptor and cytoplasmic protein tyrosine kinases to participate in the signal transduction from the cell surface to the nucleus (By similarity). Positively regulates MAPK signal transduction pathway. Dephosphorylates GAB1, ARHGAP35 and EGFR. Dephosphorylates ROCK2 at 'Tyr-722' resulting in stimulation of its RhoA binding activity. Dephosphorylates CDC73 (By similarity). Dephosphorylates SOX9 on tyrosine residues, leading to inactivate SOX9 and promote ossification (By similarity). H2O + O-phospho-L-tyrosyl-[protein] = L-tyrosyl-[protein] + phosphate Inhibited by orthovanadate, molybdate and spermidine. Optimum pH is 7.0-7.5 (isoform 1). Optimum pH is 8.5 (isoform 2). Interacts with phosphorylated SIT1, LIME1, BCAR3 and MZPL1. Interacts with FCRL4, FCRL6, ANKHD1, SHB, INPP5D/SHIP1 and CD84 (By similarity). Interacts with MILR1 (tyrosine-phosphorylated). Interacts with FLT1 (tyrosine-phosphorylated), FLT3 (tyrosine-phosphorylated), FLT4 (tyrosine-phosphorylated), KIT and GRB2 (By similarity). Interacts with PTPNS1. Interacts with KIR2DL1; the interaction is enhanced by ARRB2. Interacts (via SH2 domain) with TEK/TIE2 (tyrosine phosphorylated) (By similarity). Interacts with GAB2 (By similarity). Interacts with TERT; the interaction retains TERT in the nucleus. Interacts with PECAM1 and FER. Interacts with EPHA2 (activated); participates in PTK2/FAK1 dephosphorylation in EPHA2 downstream signaling. Interacts with PDGFRA (tyrosine phosphorylated). Interacts with PDGFRB (tyrosine phosphorylated); this interaction increases the PTPN11 phosphatase activity (By similarity). Interacts with ROS1; this mediates PTPN11 phosphorylation. Interacts with CEACAM1 (via cytoplasmic domain); this interaction depends on the monomer/dimer equilibrium and is phosphorylation-dependent (By similarity). Interacts with MPIG6B (via ITIM motif) (By similarity). Interacts with SIGLEC10 (By similarity). Interacts with CLEC12B (via ITIM motif); this interaction triggers dephosphorylation and activation of PTPN11. Expressed in brain, muscle and lung. The SH2 domains repress phosphatase activity. Binding of these domains to phosphotyrosine-containing proteins relieves this auto-inhibition, possibly by inducing a conformational change in the enzyme. Phosphorylated on Tyr-542 and Tyr-580 upon receptor protein tyrosine kinase activation; which creates a binding site for GRB2 and other SH2-containing proteins. Phosphorylated upon activation of the receptor-type kinase FLT3. Phosphorylated upon activation of the receptor-type kinase PDGFRA. Phosphorylated by activated PDGFRB (By similarity). Belongs to the protein-tyrosine phosphatase family. Non-receptor class 2 subfamily.