p38 MAPK

p38 mitogen activated protein kinase (p38 MAPK) is one of four distinct subgroups of the family of serine/threonine specific mitogen protein kinases (MAPK) [1][2]. They are critical in the cellular interpretation and response to extracellular stimuli, such as growth factors, environmental stress  and inflflammatory cytokines, which is reflected in their conservation over evolutionary time (Figure 1) [3] [4]. The alpha form of p38 MAPK (p38α) was amongst the first MAPKs to be discovered (along with ERK1 and ERK2 – extracellular regulated kinases, and JNK1) [5]. These kinases show 60-70% structural similarity, with key differences occurring in the amino acid sequence and size of the activation loop [5]. These kinases also share an activation motif (TXY), and the dual phosphorylation of threonine and tyrosine residues results in kinase activation [5]. The activation motif varies between different MAP kinases – for ERKs, X is glutamate; for JNKs, X is proline; and for p38 MAPKs, X is glycine [5].

 

p38 MAPK specifically can be described as a “nexus” of the signal transduction pathway [1]. p38 MAPK is one of four subgroups that make up MAP kinases, first isolated as a 38 kDa protein in which a tyrosine residue underwent rapid phosphorylation in response to lipopolysaccharide stimulation (LPS) [1]. LPS triggers a response in mammalian cells, resulting in protein kinase cascades that activate gene expression [6]. Moreover, p38 MAPK has four splice variants – alpha, beta, gamma and delta (Figure 1). p38α and p38β are ubiquitously expressed in all tissues [1]. Each isoform of p38 MAPK shares approximately 60% similarity with other p38 MAPK isoforms, and shares 40%-45% identity to the other three MAP kinase subgroups [1]. p38α is usually expressed at high levels in tissue, whereas p38β is expressed at lower levels. p38γ and p38δ on the other hand are only expressed in specific tissues, in comparison to the ubiquitous expression of p38α and p38β [3].

 

p38 MAPKs can be activated by a MAPKK-dependent mechanism, or a MAPKK-independent mechanism. The MAPKK-dependent mechanism involves activation by two main upstream MAP kinase kinases (MKK3 and MKK6), with additional assistance in the activation of p38α and p38δ in specific cells by MKK4 [1]. MAPKK-independent activation involves an interaction between TAB1 and p38 MAPK, resulting in the autophosphorylation of p38α [1].

 

The p38α pathway is responsible for a number of important functions, giving rise to many attributed to p38 MAPKs [7]. For example, the p38α pathway integrates signals that balance cell proliferation and differentiation, or induce apoptosis, thereby regulating tissue homeostasis [7]. This is crucial to our understanding of various pathologies associated with p38α signalling, where p38α activation can facilitate the survival and proliferation of tumour cells responsible for progression of certain types of cancers, as well as assisting the survival of tumour cells after chemotherapy [7]. In this way, tumorigenesis can be regulated by the p38α pathway according to cell type and the stage of development of the tumour [7].

 

 

References:

 

1. Zarubin T, Han J. Activation and signaling of the p38 MAP kinase pathway. Cell Res. 2005;15(1):11–8. 

http://www.ncbi.nlm.nih.gov/pubmed/15686620

2. Widmann C, Gibson S, Jarpe MB, Johnson GL. Mitogen-activated protein kinase: conservation of a three-kinase module from yeast to human. Physiol Rev. 1999;79(1):143–80.

http://www.ncbi.nlm.nih.gov/pubmed/9922370

3. Gupta J, Nebreda AR. Roles of p38α mitogen-activated protein kinase in mouse models of inflammatory diseases and cancer. FEBS J. 2015;282(10):1841–57.

http://www.ncbi.nlm.nih.gov/pubmed/25728574

4. Cuadrado A, Nebreda AR. Mechanisms and functions of p38 MAPK signalling. Biochem J. 2010;429:403–17.

http://www.ncbi.nlm.nih.gov/pubmed/20626350

5. Kumar S, Boehm J, Lee JC. p38 MAP kinases: key signalling molecules as therapeutic targets for inflammatory diseases. Nat Rev Drug Discov. 2003;2(9):717–26.

http://www.ncbi.nlm.nih.gov/pubmed/12951578

6. Han J, Lee JD, Bibbs L, Ulevitch RJ. A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells. Science (80- ). 1994;265(5173):808–11.

http://www.ncbi.nlm.nih.gov/pubmed/7914033

7. Igea A, Nebreda AR. The stress kinase p38 α as a target for cancer therapy. Cancer Research. 2015. p. 3997–4002.

http://www.ncbi.nlm.nih.gov/pubmed/26377941