Protein Kinase C in the Transduction of Signals Toward and within the Cell Nucleus

Abstract

The protein kinase C (PKC) family comprises at least 12 (mammalian) isoforms (Dekker and Parker, 1994) which differ in structure and enzymic properties. The single polypeptide chains of all isoforms contain conserved (C1—C4) and variable (V1—V5) regions, and are composed of a catalytic domain and a regulatory domain The catalytic domain is active without cofactors after proteolytic removal of the regulatory domain by cleavage in the V3 region. The catalytic domain contains typical protein kinase sequences such as, e.g. the glycine-rich ATP-binding motif present in the cAMP-dependent protein kinase and many other kinases. The regulatory domain, responsible for the cofactor dependence, contains an autoinhibitory pseudosubstrate region and sequences mediating the interactions with phospholipid and the activator diacylglycerol. Based on their structure, the members of the PKC family can be classified into three groups. The conventional or classical isoforms (cPKCs α, β I/II and γ) meet the original definition of PKC as Ca2+- and phospholipiddependent protein kinase. The Ca2+ dependence of these isoforms is mediated by the C2 region. The novel isoforms [nPKCs δ, e,η(L), θ,δ and μ]lack this region, resulting in Ca2+ independence. The atypical forms (aPKCs ζ, ι and λ) are characterized by lacking one of the two cysteine-rich zinc-finger regions present in the other isoforms. These isoforms are not able to bind and cannot be activated by phorbol esters. The novel and the atypical PKC isoforms can also be combined under the term ‘nonconventional’ isoforms. For a detailed discussion of the structural aspects of the various PKC isoforms and their biochemical properties, the reader is referred to a number of excellent reviews (Nishizuka, 1988; Stabel and Parker, 1991; Azzi et al., 1992; Hug and Sarre, 1993).