Research Programmes
Molecular Medicine
Cell signalling
Carme Caelles
Group Leader
Professor (Biochemistry and Molecular Biology Dept.- UB)
Office Tel : +34 93 403 71 30
Lab Tel : +34 93 403 71 31
e-mail : carme.caelles
irbbarcelona.org
Background
Cells are subjected to a myriad of signals, from the extracellular environment or generated endogenously. These signals trigger a variety of pathways, in which regulatory and cross-talk mechanisms operate to orchestrate an appropriate cellular response.
The interaction between the glucocorticoid receptor (GR), a member of the nuclear hormone receptor (NR) superfamily, and the Jun N-terminal kinase (JNK)/AP-1 signalling pathway is paradigm of cross-talk between two major signal transduction pathways. In addition, this cross-talk may underlie the pharmacological actions of glucocorticoids and also the resistance to glucocorticoid treatment frequently observed in vivo.
Protein phosphorylation cascades are a common feature in signalling pathways, including those involved in the regulation of the processes that lead to the division and multiplication of eukaryotic cells. For example, several protein kinase families, such as Aurora, Polo and NIMA/Nek kinases, collaborate with CDK1 in the initiation and execution of cell mitosis. Of these, the least studied are the NIMA kinases, or Neks, a family that is emerging as a central regulator of microtubule machinery, including the mitotic spindle.
Research Interests
Our group studies the regulatory and cross-talk mechanisms that underlie signal transduction.
We examine the mechanisms that underlie the inhibition of JNK by these NRs as well as the physiological and/or pharmacological actions (such as anti-inflammatory and anti-diabetic actions, respectively) derived from this ligand-mediated inhibitory activity. We also address the function and regulation of Nercc1 Nek6/7 in relation to other mitotic signalling cascades, and examine whether are associated with some of the mitotic aberrations observed in cancer cells.
Research Lines
Regarding the study of the cross-talk between GR or PPAR-γ, and the JNK/AP-1 pathway, we examine the molecular mechanisms underlying these interactions. These two cross-talk mechanisms are negative and occur in both directions, that is, activation of either one of these NRs down-regulates the JNK/AP-1 signalling pathway and vice versa. Using genetically modified mice, we study the antagonism of JNK/AP-1 by these NRs, as a mediator of the pharmacological actions of their ligands. In this regard, glucocorticoids display anti-inflammatory, anti-proliferative and immunosuppressive properties, and thiazolidinediones, which are synthetic ligands of PPAR-γ, are insulin sensitizer agents in clinical use for the treatment of type 2 diabetes. In the context of the mutual interference between these pathways, we analyze the involvement of the exacerbated activity of the JNK/AP-1 signal transduction pathway, observed in some disorders such as rheumatoid arthritis or asthma, in the decreased therapeutic response to glucocorticoids. On the basis of this study, we are currently designing and assaying add-on therapies to remediate this lack of response and/or to potentiate their pharmacological profile.
Our studies of mitotic pathways comprising the NIMA/Nek family of mitotic protein kinases seek to identify the cellular signals that regulate the activity of the Nercc1/Nek6/7 cassette though the cell cycle, and therefore to determine how Nercc1 activity is controlled at the molecular level and how this control is related to other mitotic signalling events. We also aim to determine the substrates and physiological functions of these kinases in relationship to the centrosome and mitotic microtubule machinery. In addition, we study whether Nercc1, Nek6 and Nek7 collaborate in the distinct molecular processes (such as the onset of aneuploidy) that lead to transformation and cancer. We also address whether the specific inhibition of these protein kinases could be used therapeutically as an anti-mitotic strategy.
Funding
This group receives financial support from the following sources:
- Fundació La Marató de TV3 ("La Marató de TV3" Foundation)
- Plan Nacional I+D+I, Ministerio de Educación y Ciencia (Ministry of Science and Education)
- Marie Curie International Reintegration Grant. European Commission
- Generalitat de Catalunya (Government of Catalonia)
More info
Cell signalling
IFN-γ-mediated inhibition of MAPK phosphatase expression results in prolonged MAPK activity in response to M-CSF and inhibition of proliferation
Valledor AF, Arpa L, Sanchez-Tillo E, Comalada M, Casals C, Xaus J, Caelles C, Lloberas J and Celada A
Blood, 112 (8), 3274-3282 (2008)
Selective roles of MAPKs during the macrophage response to IFN-gamma
Valledor AF, Sánchez-Tilló E, Arpa L, Park JM, Caelles C, Lloberas J and Celada A
J Immunol, 180 (7), 4523-4529 (2008)
The NIMA-family kinase Nek6 phosphorylates the kinesin Eg5 at a novel site necessary for mitotic spindle formation
Rapley J, Nicolàs M, Groen A, Regué L, Bertran MT, Caelles C, Avruch J and Roig J
J Cell Sci, 121 (23), 3912-3921 (2008)
Genetic analysis of p38 MAP kinases in myogenesis: fundamental role of p38alpha in abrogating myoblast proliferation
Perdiguero E, Ruiz-Bonilla V, Gresh L, Hui L, Ballestar E, Sousa-Victor P, Baeza-Raja B, Jardi M, Bosch-Comas A, Esteller M, Caelles C, Serrano AL, Wagner EF and Munoz-Canoves P
EMBO J, 26 (5), 1245-1256 (2007)
Hypoglycemic action of thiazolidinediones/peroxisome proliferator-activated receptor gamma by c-Jun NH2-terminal kinase pathway
Díaz-Delfín J, Morales M and Caelles C
Diabetes, 56 (7), 1865-1871 (2007)
A MAPK docking site is critical for downregulation of Capicua by Torso and EGFR RTK signaling
Astigarraga S, Grossman R, Diaz-Delfin J, Caelles C, Paroush Z and Jimenez G
EMBO J, 26 (3), 668-677 (2007)
JNK1 is required for the induction of Mkp1 expression in macrophages during proliferation and lipopolysaccharide-dependent activation
Sanchez-Tillo E, Comalada M, Xaus J, Farrera C, Valledor AF, Caelles C, Lloberas J and Celada A
J Biol Chem, 282 (17), 12566-12573 (2007)
Active Nercc1 protein kinase concentrates at centrosomes early in mitosis and is necessary for proper spindle assembly
Roig J, Groen A, Caldwell J and Avruch J
Mol Biol Cell, 16 (10), 4827-4840 (2005)
Assays to measure stress-activated MAPK activity
Caelles C and Morales M
Methods Mol Biol, 282, 145-156 (2004)
A mitotic cascade of NIMA family kinases. Nercc1/Nek9 activates the Nek6 and Nek7 kinases
Belham A, Roig J, Caldwell JA, Aoyama Y, Kemp BE, Comb M and Avruch J
J Biol Chem, 278 (37), 34897-34909 (2003)
Neuroprotective action of flavopiridol, a cyclin-dependent kinase inhibitor, in colchicine-induced apoptosis
Jorda EG, Verdaguer E, Canudas AM, Jimenez A, Bruna A, Caelles C, Bravo R, Escobedo E, Pubill D, Camarasa J, Pallas M and Camins A
Neuropharmacol, 45 (5), 672-683 (2003)
Glucocorticoid receptor-JNK interaction mediates inhibition of the JNK pathway by glucocorticoids
Bruna A, Nicolas M, Muñoz A, Kyriakis JM and Caelles C
EMBO J, 22 (22), 6035-6044 (2003)
Cell signalling
Carme Caelles
Group Leader
Professor (Biochemistry and Molecular Biology Dept.- UB)
Office Tel : +34 93 403 71 30
Lab Tel : +34 93 403 71 31
e-mail : carme.caellesirbbarcelona.org
Research Associate
Joan Roig Amorós
tel +34 93 403 71 31
joan.roigirbbarcelona.org
PhD Students
Laura Regué Barrufet
tel +34 93 403 71 31
laura.regueirbbarcelona.org
Mª Teresa Bertran Domingo
tel +34 93 403 71 31
teresa.bertranirbbarcelona.org
Kader Cavusoglu
tel +34 93 403 71 31
kader.cavusogluirbbarcelona.org
Rodrigo Gatica
tel +34 93 403 71 31
rodrigo.gaticairbbarcelona.org
Jordi Lanuza
tel +34 93 403 71 31
jordi.lanuzairbbarcelona.org
Giuseppe Pulice
tel +34 93 403 71 31
giuseppe.puliceirbbarcelona.org
Sara Sdelci
tel +34 93 403 71 31
sara.sdelciirbbarcelona.org
Postdoctoral Fellow
Neus Teixidó
tel +34 93 403 71 31
neus.teixidoirbbarcelona.org
Lab Technician
Cristina Vila Rius
tel +34 93 403 71 31
cristina.vilairbbarcelona.org
Cell signalling
- 8 September 2007
El País (Salud)
La inflamación, un arma de doble filo - 2 July 2007
Gaceta Médica Digital
Combatir la inflamación ayuda a tratar el cáncer - 1 July 2007
Revista Biomédica
La inflamación está en el origen y la progresión de enfermedades como la diabetes o el cáncer - 28 June 2007
Diario Médico
Tratar la inflamación es tan necesario como atacar a las células cancerosas - 18 June 2007
Institute News
Inflammation is at the origin and progression of diseases such as diabetes or cancerIRB Barcelona and Fundación BBVA have invited fifteen international researchers to discuss new scientific evidence associating chronic inflammation with a long list of diseases.Cancer and diabetes are the latest additions to this list.
- 25 June 2007
INFLAMMATION AND CHRONIC DISEASEBarcelona, Spain. 25 - 27 June, 2007
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