Regulatory subunits

FIGURE 15.7 Cyclic AMP-dependent protein kinase (also known as PKA) is a 150- to l70-kD R9C9 tetramer in mammalian cells. The two R (regulatory) subunits bind cAMP ( = 3 X 10 M) cAMP binding releases the R subunits from the C (catalytic) subunits. C subunits are enzymatically active as monomers. 

Insulin Receptor. Figure 1 Structure and function of the insulin receptor. Binding of insulin to the a-subunits (yellow) leads to activation of the intracellular tyrosine kinase ((3-subunit) by autophosphorylation. The insulin receptor substrates (IRS) bind via a phospho-tyrosine binding domain to phosphorylated tyrosine residues in the juxtamembrane domain of the (3-subunit. The receptor tyrosine kinase then phosphorylates specific tyrosine motifs (YMxM) within the IRS. These tyrosine phosphorylated motifs serve as docking sites for some adaptor proteins with SRC homology 2 (SH2) domains like the regulatory subunit of PI 3-kinase. 

Tyrosine phosphorylated IRS interacts with and activates PI 3-kinase [3]. Binding takes place via the SRC homology 2 (SH2) domain of the PI 3-kinase regulatory subunit. The resulting complex consisting of INSR, IRS, and PI 3-kinase facilitates interaction of the activated PI 3-kinase catalytic subunit with the phospholipid substrates in the plasma membrane. Generation of PI 3-phosphates in the plasma membrane reemits phospholipid dependent kinases (PDKl and PDK2) which subsequently phosphorylate and activate the serine/threonine kinase Akt (synonym protein... 

Smooth muscle myosin phosphatase contains tree subunits, a 110-130 kDa myosin phosphatase targeting and regulatory subunit (MYPT1), a 37 kDa catalytic subunit (PP-1C) and a 20 kDa subunit of unknown function. 

Family of enzymes phosphorylating phosphatidylinositol (Ptdlns), PtdIns(4)phosphate, and PtdIns(4,5)phosphate in the 3-position. The Ptdlns(3 phospholipids are second messengers in processes like cell growth, cytoskeletal rearrangement, and vesicular transport. PI 3-kinases are heterodimers composed of a catalytic and a regulatory subunit. The enzymes are activated by insulin, many growth factors, and by a variety of cytokines. Their activity can be inhibited by wortmannin and LY294002. 

All class I PI3Ks are heterodimeric enzymes composed of a 110 kDa catalytic subunit (with the isoforms pi 10 a,(3,5 or y) that associates with a regulatory subunit. Although the class I PI3Ks are capable of phosphorylating Ptdlns, PtdIns(4)P and PtdIns(4,5)P2 in vitro, it appears that they only use PtdIns(4,5)P2 as a substrate in vivo. Receptor-induced formation of Ptdlns... 

Protein kinase A (PKA) is a cyclic AMP-dependent protein kinase, a member of a family of protein kinases that are activated by binding of cAMP to their two regulatory subunits, which results in the release of two active catalytic subunits. Targets of PKA include L-type calcium channels (the relevant subunit and site of phosphorylation is still uncertain), phospholam-ban (the regulator of the sarcoplasmic calcium ATPase, SERCA) and key enzymes of glucose and lipid metabolism. 

Regulatory subunits (e.g., PP1, PP2A, PP2B note that... 

Calcium-dependent regulation involves the calcium-calmodulin complex that activates smooth muscle MLCK, a monomer of approximately 135 kDa. Dephosphorylation is initiated by MLCP. MLCP is a complex of three proteins a 110-130 kDa myosin phosphatase targeting and regulatory subunit (MYPT1), a 37 kDa catalytic subunit (PP-1C) and a 20 kDa subunit of unknown function. In most cases, calcium-independent regulation of smooth muscle tone is achieved by inhibition of MLCP activity at constant calcium level inducing an increase in phospho-rMLC and contraction (Fig. 1). 

Figure 1. The cell cycle as a Cdc2 cycle. Progression through the eukaryotic cell cycle is sensitive to the phosphorylation state of Cdc2. A block to DNA synthesis (S) prevents dephosphorylation, and hence activation, of Cdc2. Impaired spindle function will prevent deactivation of Cdc2 and thus blocks exit from M phase (Hoyt et al., 1991 Li and Murray, 1991 reviewed in Nurse, 1991). Exit from M phase requires destruction of the regulatory subunit, Cyc B. Dephosphorylation of Cdc2 at thr-161 may act to destabilize the Cdc2/Cyc B complex and thus allow the ubiquitination of Cyc B followed by its destruction.

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