Cell signaling is an adaptive response of cells to extracellular signals.  Transduction of the signal within the cell can lead to several processes such as production or degradation of a specific protein, programed cell death or cell division.  This process occurs mainly via protein-protein interactions and phosphorylation and de-phosphorylation of specific protein substrates held respectively by kinases and phosphatases. Protein phosphorylation is the transfer of a phosphoryl group of ATP to specific amino acids, normally serines, threonines and tyrosines in eukaryotes. De-phosphorylation is the removal of the phosphoryl group from these amino acids. In cells these are key reactions and part of physiological and pathological processess.  In several pathologies kinases have altered activity and expression making them good drug targets. In fact, pharmaceutical companies have dedicated large efforts to find new specific modulators for the different kinases, which has been very challenging due to the conserved nature of these enzymes, limiting the specificity of action of modulators. The main interest of my lab is to understand how the regulation of expression of specific kinases occurs, as well as the specificity of interactions of these enzymes with their respective substrates. Specifically, we are studying expression and mutations of members of the protein kinase C (PKC) family of serine/ threonine kinases and TrkA a tyrosine kinase coupled to the high affinity nerve growth factor receptor (NGF), in physiological and pathological processes such as cancer and insensitivity to pain.  To this end we are using biochemical, molecular and cell biology techniques as well as molecular modeling.

Lab Technician

Posdoctoral Researcher

Identification of PKCλ signaling binding partners in pancreatic cancer
Ductal adenocarcinoma is the most common malignancy of the pancreas and is characterized by a remarkable resistance to most of the available treatments, including chemotherapy, radiotherapy and molecularly targeted therapy. One of the hallmarks in pancreatic cancer is invasion and metastasis upon early onset of disease spreading. Atypical protein kinase C (aPKC), serine/threonine kinases, have been described as key components in determining cell polarity by interacting with the Partitioning defective complex (Par complex). Specifically, with regards to Pancreatic cancer, previous studies have shown that PKCλ plays an important role in invasion and metastasis. Furthermore, PKCλ is significantly over-expressed in this type of cancer and inhibition of PKCλ blocks Pancreatic Ductal Adenocarcinoma (PDAC) cell growth and tumorigenicity as well as pancreatic tumor angiogenesis and metastasis. However, the molecular mechanisms by which PKCλ leads to tumorigenesis are still unclear. PKCλ available inhibitors are not specific and lead to drug resistance possibly because frequent mutations are found in the catalytic domain of the kinase. Specifically inhibiting depict protein-protein interactions of PKCλ with target proteins could be more effective. Thus, in the present project we intend to identify and characterize PKCλ substrates and binding proteins and determine the signaling pathways that are involved in the loss of epithelial polarity, migration and invasion of pancreatic cancer cells.

Doctorate Students

Master Students

Antibodies against active PKCs
Considered a key regulatory element in cell function, protein kinases (PK) are capable of orchestrating the activity of the majority of biological processes.  A dysregulation of kinase activity/ expression leads to several pathological processes such as cancer and insensitivity to pain.   Thus, it is clear that investigating the dynamics of kinases is fundamentally important in the characterization of signal transduction pathways in cancer and other diseases. The goal of my project is to develop new antibodies that in situ analysis of Protein kinase C (PKC) activity, by specifically developing a tool that can discriminate between active and inactive PKC in different tissue samples and cell cultures.

Signalling pathways regulated by TrkA
Mutations found in the tyrosine kinase receptor of tropomyosine kinase (TrkA), a kinase coupled to the high affinity nerve growth fator receptor (NGF) decrease pain sensitivity in Naked mole rat. My project aims at studying the diferente signaling pathways of TrkA activated by NGF comparing wild type human protein with a protein containing mutations found in NMR. We also aim to detect new TrkA substrates developing methods that can detect substratos of serine/threonine and tyrosine kinases.

Effect of TrkA mutations on cell signaling pathways
Congenital insensitivity to pain with anhidrosis (CIPA) has as a main sympton lack of sensorial perception, and may presente diferente levels of lack of nociceptive and sympathetic nerves. One of the main factors that lead to disease are loss of function of the receptor of tropomyosine kinase (TrkA). There are several mutations that lead to  CIPA, some in the kinase domain, these will be studied in my project and we will evaluate possible diferences in signal transduction pathways of assim avaliarmos ( (PLCg, PI3K and Erk) caused by these mutations.