Protein kinases and phosphatases in the control of cell fate

Abstract

Protein phosphorylation controls many aspects of cell fate and is often deregulated in pathological conditions. Several recent findings have provided an intriguing insight into the spatial regulation of protein phosphorylation across different subcellular compartments and how this can be finely orchestrated by specific kinases and phosphatases. In this review, the focus will be placed on (i) the phosphoinositide 3-kinase (PI3K) pathway, specifically on the kinases Akt and mTOR and on the phosphatases PP2a and PTEN, and on (ii) the PKC family of serine/threonine kinases. We will look at general aspects of cell physiology controlled by these kinases and phosphatases, highlighting the signalling pathways that drive cell division, proliferation, and apoptosis.

Figure 1

PI3K signalling pathway: The phosphatidylinositol 3-kinase (PI3K) signalling pathway begins with PI3K activation by receptor tyrosine kinases after growth factors or insulin stimulation. PI3K activity phosphorylates and converts the lipid second messenger phosphatidylinositol 4,5-bisphosphate (PIP2—indicated by red phosphoinositide) into phosphatidylinositol 3,4,5-triphosphate (PIP3—indicated by green phosphoinositide), with consequent double phosphorylation/activation of Akt kinase. Akt promotes cell proliferation and survival by phosphorylation/inhibition of several proapoptotic targets (hold by the red dotted line), or by activation of mTOR complex 1, an important regulator of several processes, such as autophagy, angiogenesis and protein synthesis. Protein phosphatase 2a (PP2a) family members are able to dephosphorylate/inhibit Akt, favouring apoptosis also by direct dephosphorylation of Bcl-2. The tumour suppressor phosphatase PTEN negatively regulates PI3K signalling by dephosphorylating PIP3, converting it back to PIP2. A mono-uniquitinated/active form of PTEN is able to translocate into the nucleus, promoting DNA repair, cell cycle arrest and chromosome stability.

Figure 2

(a) Domain structure of protein kinase C (PKC) isoforms. All PKC family members comprise four conserved domains (C1–4) and five variable (V) domains. All isoforms contain a pseudosubstrate domain (PS) that maintains PKC in a catalytically inactive form. The C1 domains are the molecular sensors of phorbol 12-myristate 13-acetate (PMA)/diacylglycerol (DAG) in cPKC and nPKC isoforms. Atypical PKCs have only one C1 domain and are unable to bind DAG. The C2 domains function as calcium-dependent phospholipid binding modules in cPKCs, whereas nPKC C2 domains do not bind calcium, and aPKCs are lacking these domains. (b) PKCs signalling. The diagram summarizes current knowledge of the PKCs signalling pathways. Full and further details are provided in the text.

Figure 3

Summary of Akt, mTOR, PP2a, PTEN, and PKC intracellular localization and functions: each table summarized the various physiological processes regulated in the different subcellular compartments. Full and further details are provided in the text.