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Fig. 1. The ordering of the two universal steps in CDK activation is variable. In pathway 1, binding of cyclin to form an inactive complex precedes phosphorylation within the activation loop by a CAK. This is the obligate pathway for activation of CDK1–cyclin-B complexes by CDK7 in metazoan cells (Fisher and Morgan, 1994; Desai et al., 1995). The steps are switched around in pathway 2, in which a CAK phosphorylates the T-loop of a monomeric CDK, which only becomes active upon subsequent binding of a cyclin. This is the preferred, but not obligate, pathway for activation of CDKs by the fungal CAKs: Cak1 (Ross et al., 2000) and Csk1 (Tsakraklides and Solomon, 2002). It is also a pathway available to metazoan CDK2, which can be efficiently phosphorylated by CDK7 in the absence of a cyclin partner (Fisher and Morgan, 1994; S. Larochelle and R.P.F., unpublished).





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