| We show that phosphoinositide 3 ( PI 3 ) kinase associates with 4 tyrosine phosphorylated proteins in primary human erythroid progenitors , namely insulin receptor substrate 2 ( IRS 2 ) , Src homology 2 domain containing inositol 5 ' phosphatase ( SHIP ) , Grb 2 associated binder 1 ( Gab 1 ) , and the Epo receptor ( EpoR ) . ^^^ Using different in vitro systems , we demonstrate that 3 alternative pathways independently lead to Epo induced activation of PI 3 kinase and phosphorylation of its downstream effectors , Akt , FKHRL 1 , and P70S6 kinase : through direct association of PI 3 kinase with the last tyrosine residue ( Tyr 479 ) of the Epo receptor ( EpoR ) , through recruitment and phosphorylation of Gab proteins via either Tyr 343 or Tyr 401 of the EpoR , or through phosphorylation of IRS 2 adaptor protein . ^^^ |