The p MAPK subfamily can be further

The p38 MAPK subfamily can be further divided into two distinct subsets, first as p38α and p38β and secondly as p38γ and p38δ, based on expression pattern, specificity of substrate and sensitivity to pharmacological inhibitors [5]. p38α and p38β are 75% identical based on their amino citco level whereas p38γ and p38δ are 70% similar to each other while 61% and 62% identical to p38α respectively [6]. In vitro and in vivo assays demonstrated that p38 inhibitors, SB203580 and SB202190 could inhibit only p38α and p38β while these drugs had no effect on p38γ and p38δ [7]. Reports suggest that microtubule-associated protein Tau, scaffold proteins α1-syntrophin, SAP90/PSD95 and SAP97/hDlg are better substrates for p38γ and p38δ than p38α and p38β in vitro [8], [9], [10], [11], [12]. p53 functions as a tumor suppressor gene, playing a major role in cellular death in response to DNA damage [13]. Cells having p53 mutated or compromised state, activation of ATM, ATR, Chk1, p38 MAPK/MK2 and caspase 3 takes place in upon DNA damage. In p53 mutated tumor cells, p38-MK2 pathway plays an important role in DNA damage response [14]. On the other hand, DNA damage response and repair options have crucial links with chromosomal integrity. The global genome maintenance and repair is regulated by functional telomeres [15]. An important role is played by telomeric shelterin complex in the molecular crosstalk between DNA damage sensing proteins notably ATM which in turn activate p38 [14]. Increased formation of guanine (8-oxodG) adducts in the G-rich telomere repeat of telomeric DNA causes shortening of telomeres and strand breaks from halted telomere replication process. [16]. One of the major reactions to cellular stress including DNA damage and dysfunctional telomere is activation of p38 pathway leading to cell cycle arrest and apoptosis [3], [17].
p38 MAPK signaling The p38 MAPK pathway is activated in response to stress [18]. The 4 isoforms of p38 gets activated by phosphorylation of Threonine-Glycine-Tyrosine (TGY) dual phosphorylation motif in their activation loop [19], [20], [21]. MAPK Kinases, MKK3 and MKK6 are upstream activators of p38 that are responsible for phosphorylation and are themselves activated by various MAPKKKs (MAPK Kinase Kinases) [21]. These are induced by stresses which can either be physical or chemical, such as hypoxia, UV irradiation, ionizing radiation (IR) cytokines like IL-1 and TNF-α [22]. The exact molecular mechanism of oxidative stress induced activation of MAPK pathway is not clearly understood. p38 MAPK pathway is also activated through G- protein coupled receptor (GPCR) which involves TAO1/2/3 by downstream activation of MKK3/6 [23]. In specific cases p38 can also be activated by MKK4 [24]. In addition of being activated by upstream kinases, there is a MKKK/MKK independent mechanism by which p38 MAPK can be activated by auto-phosphorylation which was associated with ischemic heart and immunological processes [25], [26], [27]. This activation pathway involves the interaction of p38 with TAB1 [transforming growth factor-β-activated protein kinase 1 (TAK1) −binding protein] followed by auto-phosphorylation of p38α [28]. p38 MAPK does not gets activated in fibroblast or epithelial cells by this MKKK/MKK independent mechanism under the same conditions [29]. Though the MKK-independent p38 activation sneeds to be further investigated but there is report that support the role of TAB1 in p38 activation [29]. p38α is known to be activated in T cells by another MKKK/MKK independent mechanism. In this mechanism p38α gets activated by an alternative mechanism where T cell antigen receptor (TCR)-mediated stimulation activates proximal tyrosine kinases like Lck. It causes phosphorylation of p38α on a non-canonical activating residue, Tyr323 that leads to changes in the structural conformation of p38α. Structurally changed p38α phosphorylates third party substrates as well as its own TGY motif [27]. Schematic representation of p38 MAPK signaling pathway is depicted in.