**5. Apoptosis inhibition and infection**

and neurotransmitters through binding to different G-protein coupled receptors, tyrosinekinase receptors, and ion channels. Then, signal transduction continues with an adaptor protein that transmits the signal to a MAP3K of which several have been described for ERK such as Raf-1B-Raf, A-Raf, and TPL2 [62]. Following the described phosphorylation pattern (MAPKKK → MAPKK → MAPK), the stimulus activates MAPKKK (i.e., Raf-1), which in turn phosphorylates MEK1 and MEK2 (both MAPKK) and these finally phosphorylate

One of the upmost actions of MAPK is the activation of transcription factors, which regulate the expression of genes that lead to crucial molecular events in the cell regarding growth, proliferation, inflammatory cytokine production, and apoptotic cell death [56]. In relation to apoptosis, a key participant is JNK that plays its role through two different mechanisms. The first one is related to nuclear events in which JNK is translocated to the nucleus and activates c-Jun and other transcription factors that promote proapoptotic gene expression, through p53/73 or c-Jun/AP1-dependent mechanisms [70, 71]. The second mechanism relates to JNK activation and translocation to the mitochondria, where it promotes the phosphorylation of protein 14–3-3, a protein that normally inhibits Bax by being bound to it. As protein 14–3-3 is phosphorylated, Bax is released and translocates to the interior of the mitochondria where it oligomerizes and forms pores in the mitochondrial membrane with the subsequent release of cytochrome c and apoptosis induction through the intrinsic pathway. Apart from these two mechanisms, JNK can also phosphorylate "BH3-only" family members, whose antiapoptotic effect inhibits Bcl-2 and Bcl-xL and is also involved in the posttranslational modifications of Bid and Bim, both of which induce Bad and Bax activity [70, 71]. Another MAPK deeply involved in apoptosis is p38, which in many times is simultaneously activated with JNK [72]. p38 exerts its central role in apoptosis through the activation of proapoptotic proteins, mainly BimEL, BAD, and Bax [73–77] and simultaneously induces the inhibition of ERK and Akt antiapoptotic pathways [76, 77]. Also, p38 and JNK participate in TLR signaling pathways. These key participants of the innate immune response function as regulatory sensors of both apoptosis signaling through the induction of MAPK p38 and JNK [78, 79] and survival signals

and activate ERK1 and ERK2 [62].

100 Current Understanding of Apoptosis - Programmed Cell Death

**3.2. MAPK participation in apoptosis**

through PI3K and some Bcl-2 family members [80–82].

**inhibition**

**4. PI3K/Akt signaling pathway and its participation in apoptosis** 

and thus the assembly of the active molecule that catalyzes the conversion of PIP2

As previously mentioned, MAPK p38 and JNK play an important role in apoptosis induction. On the other hand, PI3K activation promotes cellular survival. PI3K is a heterodimer formed by a p85 regulatory subunit and a p110 catalytic subunit responsible for phosphate transfer. The signaling pathway initiated by this kinase is activated by different stimuli, with growth factors standing out among them. Once a ligand binds to the tyrosine specific tyrosine-kinase receptor, an IRS adaptor protein is activated, which in turn activates the regulatory PI3K subunit and generates a conformational change that allows the binding of the catalytic subunit

into PIP3

Apoptosis constitutes a very important defense mechanism against intracellular microorganisms [95], whom in order to survive inside cells need to inhibit the induction of apoptosis. It has been demonstrated that diverse intracellular pathogens including virus [96], bacteria [97], and protozoan parasites [98] have developed mechanisms to persist within host cells without inducing apoptosis.
