Scaffold proteins can also orient these signaling molecules to enhance the rate of signal transduction. As a result, they often have concentration-dependent biphasic effects on the biological processes they control. However, a single scaffold usually binds to one individual kinase molecule when the scaffold concentration is higher than the kinase concentration, which eventually decreases the output of the kinase cascade. Scaffold proteins function by tethering binding partners to enhance the efficiency of interaction between them, thereby increasing the effective concentration of enzymes and their substrates. Classical scaffold proteins are themselves usually not enzymatically active but have at least two binding partners with catalytic or receptor activity, and the binding partners can interact with each other in a direct or indirect way. Scaffold proteins physically assemble two or more members of a signaling pathway into a protein complex to ensure specific and efficient signaling. Therefore, GSK690693 causes abnormal glucose metabolism and hyperglycemia ( 4). For example, GSK690693 inhibits Akt kinase activity and its targets (GSK-3, FOXO, and mTOR), all of which are important for insulin signaling. Serious side-effects of Akt inhibition (including hyperglycemia, thrombocytopenia, and infections) have prevented further clinical application of these agents ( 2, 3). However, Akt plays a central role in signaling pathways that regulate cellular metabolism and inhibiting Akt kinase disrupts glucose and protein metabolism. Several Akt inhibitors, such as BIA6, GSK690693, and KP-1, inhibit proliferation and decrease chemoresistance of cancer cells by inhibiting the activity of Akt and its downstream targets, such as mammalian target of rapamycin complex 1 (mTORC1), forkhead box protein O1 (FOXO), and glycogen synthase kinase-3 (GSK-3). However, only a few Akt inhibitors have been approved by Food and Drug Administration for chemotherapy. Thus Akt has received much attention as a target for anticancer drugs. These isoforms all play a role in carcinogenesis and tumor development ( 1).Īberrant Akt activation has been detected in nearly 80% of tumors. Mammalian Akt has three isoforms: Akt1, Akt2, and Akt3, all of which share an evolutionarily conserved structure, including an NH 2-terminal PH-sequence, a kinase catalytic domain, and a COOH-terminal regulatory domain. Mammalian Akt /PKB proteins belong to a family of serine/threonine protein kinases.
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