Mitogen-activated protein kinase 9 (MAPK9), also well known as c-Jun N-terminal kinase (JNK2), is a member of MAP kinase subfamily belonging to the protein kinase superfamily. The crystal structure of human JNK2 complexed with an indazole inhibitor by applying a high-throughput protein engineering and surface-site mutagenesis approach. A novel conformation of the activation loop is observed, which is not compatible with its phosphorylation by upstream kinases. This activation inhibitory conformation of JNK2 is stabilized by the MAP kinase insert that interacts with the activation loop in an induced-fit manner. It suggest that the MAP kinase insert of JNK2 plays a role in the regulation of JNK2 activation, possibly by interacting with intracellular binding partners. JNK2 deficiency leads to reduced c-Jun degradation, thereby augmenting c-Jun levels and cellular proliferation, and suggests that JNK2 is a negative regulator of cellular proliferation in multiple cell types. JNK2 blocks the ubiquitination of tumor suppressor p53, and thus increases the stability of p53 in nonstressed cells. JNK2 negatively regulates antigen-specific CD8+ T cell expansion and effector function, and thus selectively blocking JNK2 in CD8+ T cells may potentially enhance anti-tumor immune response. Lack of JNK2 expression was associated with higher tumor aneuploidy and reduced DNA damage response. Additionally,the JNK2 protein could be a novel therapeutic target in dry eye disease, and may provide a novel target for prevention of vascular disease and atherosclerosis.
The MAPKAP kinases are a group of MAP kinase substrates which are themselves kinases. In response to activation, the MAP kinases phosphorylate downstream components on a consensus Pro-X-Ser/Thr-Pro motif. Several kinases that contain this motif have been identifed and serve as substrates for the ERK and p38 MAP kinases. Mitogen-activated protein (MAP) kinase-activated protein kinase 3, also known as MAPKAPK-3 and 3pK, is a member of the Ser/Thr protein kinase family. It is Widely expressed in human tissues, with a higher expression level observed in heart and skeletal muscle. No expression in brain. MAPKAPK-3 is unique since it was shown to be activated by three members of the MAPK family, namely extracellular-signal-regulated kinase (ERK), p38, and Jun-N-terminal kinase (JNK). It is highly activated both by mitogens and by stress-inducing agents or proinflammatory cytokines, and translocates to the cytoplasm from nucleus. MAPKAPK-3 is exclusively activated via the classical MAPK cascade, while stress-induced activation of MAPKAPK-3 is mainly mediated by p38, however the mechanism defining the specificity remains unknown.
MAPKAPK5 contains 1 protein kinase domain and belongs to the protein kinase superfamily, CAMK Ser/Thr protein kinase family. MAPKAPK5 has significant sequence homology to mitogen-activated protein kinase (MAPK)-activated protein kinase (MAPKAPK). It is widely distributed. MAPKAPK5 can be phosphorylated by extracellular-regulated kinase (ERK), and p38 kinase but not by c-jun N-terminal kinase (JNK)in vitro.Recombinant GST-MAPKAPK5 protein can phosphorylate a peptide derived from the regulatory light chain of myosin II. Phosphorylation of MAPKAPK5 by ERK and p38 kinase increased its activity by 9 and 15 fold respectively. Taken together, these data suggest that MAPKAPK5 is a novelin vitrosubstrate for ERK and p38 kinase. In response to cellular stress and proinflammatory cytokines, this kinase is activated through its phosphorylation by MAP kinases including MAPK1/ERK, MAPK14/p38-alpha, and MAPK11/p38-beta. MAPKAPK5 also mediates stress-induced small heat shock protein 27 phosphorylation.
MAPT (microtubule-associated protein tau) can produce tau proteins. Tau proteins are proteins that stabilize microtubules. They are abundant in neurons of the central nervous system and are less common elsewhere, but are also expressed at very low levels in CNS astrocytes and oligodendrocytes. When tau proteins are defective, and no longer stabilize microtubules properly, they can result in dementias such as Alzheimer's disease. Tau protein is a highly soluble microtubule-associated protein (MAP). In humans, these proteins are mostly found in neurons compared to non-neuronal cells. One of tau's main functions is to modulate the stability of axonal microtubules. Other nervous system MAPs may perform similar functions, as suggested by tau knockout mice, who did not show abnormalities in brain development - possibly because of compensation in tau deficiency by other MAPs.
Mannan-Binding Lectin Serine Protease 1 (MASP-1) belongs to the peptidase S1 family. MASP1 contains two CUB domains, one EGF-like domain, one peptidase S1 domain and two Sushi (CCP/SCR) domains. MASP1 is primarily expressed in liver. MASP1 involved in the lectin pathway of the complement, performs a key role in innate immunity by recognizing pathogens through patterns of sugar moieties and neutralizing them. MASP1 is synthesized as a zymogen and activated when it complexes with the pathogen recognition molecules of lectin pathway, the mannose-binding lectin and the ficolins. MASP1 is not directly involved in complement activation but may act as an amplifier of complement activation by cleaving complement C2 or by activating another complement serine protease, MASP2. MASP1 is also able to cleave fibrinogen and factor XIII and may may be involved in coagulation. MASP1 is inhibited by SERPING1 and A2M.
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