RESEARCH SUMMARY

The aim of our group is both to discover how members of the p38MAPK family regulate cellular function in physiological conditions and in response to environmental stresses, infection and proinflammatory cytokines, and to understand how they become deregulated in several human disease situations such as oncogenic transformation and inflammation.

In order to achieve these, our research is focused on:

1. the discovery of new substrates, interacting proteins and inhibitors for these kinases, and the study of their physiological roles using transgenic mice for the different p38 isoforms; and
2. the study of p38MAPK as a link between chronic inflammation and cancer, and also as mediators of chronic inflammatory diseases.

These studies utilize biochemical, cell biology as well as whole animal model approaches.

There are four members of the p38MAPK family (p38α, p38β, p38γ and p38δ) which are similar in amino acid sequence but differ in expression patterns, substrate specificities and sensitivities to inhibitors. During the last years our group has been centered in the elucidation of the regulation and roles of the p38MAPK family members, p38γ and p38δ. Thus, we have found that p38γ interacts and is the physiological kinase of several PDZ domain-containing proteins. In particular p38γ interacts and phosphorylates the tumor suppressor protein hDlg, regulating its association to the cytoskeleton and to nuclear protein-RNA complexes.

We are currently studying how p38γ regulates the integrity of nuclear and intercellular-junctional complexes, cell adhesion, migration and polarity, as well as cell cycle and proliferation in response to many kinds of external stimuli. A large body of evidences indicated that p38α MAPK activity is critical for the production of proinflammatory cytokines, which uncontrolled production, is a major cause of chronic inflammatory diseases. However little is know about the role of p38γ and p38δ isoforms in these processes. We are currently undertaking further studies to investigate this and also their role in the development of cancer associated to inflammation, using the genetically modified mice we have generated.