Fig. 10. Temporal model for activation of PTPα and Src during mitosis. Hypothetical time lines for phosphorylation and activation of the Cdc2–Cyclin B complex, Src and PTPα are shown which consolidate the multiple known functional and temporal relationships: (1) Cdc 25 activates the Cdc2-Cyclin B complex by dephosphorylating Thr14 and Tyr15 in Cdc2 (Kishimoto and Okumura, 1997); (2) the complex initiates nuclear envelope breakdown (Kishimoto and Okumura, 1997) and (3) phosphorylates mammalian Src at Thr36 and Ser74 (Shenoy et al., 1989; Lin, 1994); (4) these phosphorylations reduce Src SH2-pTyr527 affinity (Stover et al, 1994), thus (5) making pTyr527 more accessible for dephosphorylation (Bagrodia et al., 1991, 1994; Stover et al., 1994); (6) PTPα is activated by Ser hyperphosphorylation (this study) and (7) dephosphorylates pTyr527 by a phosphotyrosine displacement mechanism involving PTPα pTyr789 (Zheng et al., 2000); (8) both PTPα and Src are activated during metaphase (this study and Chackalaparampil and Shalloway, 1988); (9) APC/cyclosome deactivates the Cdc2–Cyclin B complex leading to anaphase (Page and Hieter, 1999); (10) the mitotic Ser/Thr Src phosphorylations are removed and Src is subsequently deactivated by rephosphorylation at Tyr527 at about the time of cytokinesis (Chackalaparampil and Shalloway, 1988), (11) probably by Csk (Sabe et al., 1994); (12) the mitotic modifications of PTPα (i.e. serine decreased Grb2 binding and enhanced specific activity) are removed during an extended period surrounding cytokinesis (this stydy). Dark colors indicate the functionally activated state. Small circles surrounding S, T or Y indicate phosphorylation of the respective amino acid types: in Cdc2, the inhibitory sites, Thr14 and Tyr15, and the stimulatory site Thr161; in mammalian Src, the mitosis-specific targets of Cdc2 phosphorylation, Thr36 and Ser74, and Tyr527; and in PTPα, Tyr789 and at least one serine site. The relative timing of all events is established except for that of activation of PTPα relative to activation of the Cdc2–Cyclin B complex, which is unknown. The absolute times of the phosphorylation of Src by Cdc2–Cyclin B and its dephosphorylation by PTPα are not known, except that they must occur sometime within an interval beginning shortly before nuclear envelope breakdown and ending at metaphase.