Leonard Girnita's Group

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Cross-talk between the receptor tyrosine kinases (RTKs) and G protein-coupled receptors (GPCRs). Functional, diagnostic and therapeutic implications for cancer.

General description: "Receptor pathology" lab, performing translational research by investigating the molecular properties and regulatory mechanisms that control the function of plasma membrane receptors under normal and pathological circumstances. The final goal is to determine potential utility of the signalling complexes involved in the RTKs/GPCRs cross talk as biomarkers or molecular targets in cancer.

Hypothesis underlying research: Signalling complexes coordinated by beta-arrestins, kinases and (de)ubiqitine ligases contribute to tumourigenesis and the progression of cancer and could be targeted in therapies.

Our hypothesis and aims

Cross-talk at multiple levels between G protein-coupled receptor and growth factor receptor pathways has a fundamental role in coordinating downstream signaling molecules and this ultimately controls development and maintenance of the malignant phenotype.

The objective of this program is to investigate the function of the signaling complexes involved in the GPCR/RTK cross-talk and determine their potential utility as potential biomarkers or therapeutic targets in cancer. Our main focus is on the signaling complexes coordinated by β-arrestins and involving kinases, ubiquitin ligases and deubiquitinating enzymes, which we hypothesize to contribute to tumourigenesis and the progression of cancer and could be targeted in therapies.

Background

Cancer is today one of the most important public health problems in Europe: there are 3.2 million new cases and 1.7 million deaths each year. With the ageing of the European population these numbers are predicted to steadily increase. Therefore research must focus on disease etiology, new medicines and therapies as well as on identification and validation of drug targets and biomarkers that aid in the prevention, early diagnosis and more tailored treatment.

In the selection leading to cancer, cancer cells make use of the normal extracellular signaling for proliferation, migration and/or antiapoptosis to gain a growth advantage over normal cells. These signals are, in part, generated by plasma membrane receptors. Our work refers to two major classes: G proteincoupled receptors (GPCR) and growth factor receptors (receptor tyrosine kinases, RTKs).

The G protein-coupled receptors (GPCRs) represent the largest (>1000) family of plasma membrane receptors and they mediate a large proportion of physiological functions. Moreover, GPCRs represent the most prominent family of validated pharmacological targets in current medical practice accounting for about 50% of all prescription drug sales worldwide. However, the involvement of GPCRs in cancer is unappreciated and their potential as therapeutic targets is scarcely exploited.

Three families of proteins coordinate the function of the GPCR: the heterotrimeric G proteins, the G proteincoupled receptor kinases (GRKs), and the β-arrestins.

The tyrosine kinase receptors (RTKs) are a related family of cell surface receptors with similar structure and functions. Although few compared with the large number of GPCR, RTKs receive particular interest for targeted therapy in cancer. Among them, IGF-1R is considered as one of the most attractive target for cancer therapy. In vivo and in vitro studies using IGF-1R antibodies, small molecule inhibitors and antisense technology have shown that IGF-1R is functionally essential for tumor cell growth and cancer cell proliferation in most if not all forms of cancer. Yet, the lessons from the clinical trials using IGF-1R antibodies indicates that tumors initially addicted to IGF-1R signaling develop rapid resistance to the therapy. To address this dilemma, it is crucial to identify the subset of patients likely to respond. Biomarkers that predict as well as tools that would enhance response to IGF-1R therapy are urgently needed.

Research line 1

Investigating the molecular mechanism of beta-arrestin/GRK-biased agonism at the IGF-1R

During the last years our lab demonstrated that β-arrestin and GRKs, proteins traditionally associated with GPCR functions, also control the IGF-1R (and possibly other RTKs) expression and signaling. In this project we aim to functionally characterize the GRKs/β-arrestin roles in controlling RTK signaling as well as their functional implications for cancer development.

Research line 2

Evaluating the beta-arrestin signaling complex as a potential diagnostic or prognostic biomarker.

β-arrestin regulates formation of a scaffolding protein that integrates IGF-1R (RTK) and GPCR signaling as well as Raf and Ras downstream signaling. Ras/Raf genes are mutated in several cancer types including melanoma, colon and pancreatic cancer. Our data indicates that the composition of the β-arrestin complex may be different in malignant cells and normal cells. Therefore, we predict that the status of the β-arrestin complex may differentiate non-transformed cells from tumour cells, and a migratory phenotype from a non-migratory phenotype.

Research line 3

GRKs/beta-arrestins as targets for receptor cross talk in cancer

Since β-arrestin plays a critical role in modulating signaling pathways emanating from many GPCR and RTKs, alterations in β-arrestin function, induced by various forms of receptor cross talk, are likely to have pronounced effects on intracellular signaling. In this project we will investigate the biological effects as well as therapeutic values of following various perturbations of β-arrestin/GRK functions.

Simultaneously we are also investigating a novel approach for cancer treatment: biasing RTK signaling through GPCR.

Dissertations

Huiyuan Zheng
Molecular function and targeting of beta-arrestins in cancer.
September 14, 2012
Abstract

Natalia Natalishvili
IGF-1R: Studies on the expression and role in transformation
May 29, 2009
Abstract

Linda Rosengren
Targeting the GH/IGF-1 axis with novel, small molcule inhibitors
October 26, 2007
Abstract

Bita Sehat
SUMO and ubiquitin: the Yin and Yang of IGF-1R function
October 25, 2007
Abstract

Mario A Economou
Uveal melanoma and macular degeneration: Molecular biology and potential therapeutic applications
September 7, 2007
Abstract

Radu Vasilcanu
Regulation of insulin-like growth factor-1 receptor expression and signaling
June 15, 2007
Abstract

Daiana Vasilcanu
IGF-1R inhibition: A tool for functional studies of insulin-like growth factor family in malignant cells
February 3, 2006
Abstract

Research funding

  • Karolinska Institutet funds
  • The Swedish Cancer Society
  • The Swedish Research Council
  • The Swedish Childhood Cancer Foundation
  • Crown Princess Margareta's Foundation for the Visually Impaired
  • Welander-Finsen Foundation
  • King Gustav V Jubilee Foundation
  • Vinnova
  • Stockholm County

Group members

Leonard Girnita, MD, PhD, Associate Professor, Group leader
Ada Girnita, MD, PhD, Senior researcher, project leader
Charlotta All-Eriksson, MD, PhD, Clinical researcher

Claire Worrall, PhD, Postdoc
Iulian Oprea, MD, PhD, Postdoc
Beklem Bostancioglu PhD, Postdoc
Naida Suleymanova, PhD student

Caitrin Crudden, PhD student
Iara Rocha Trocoli Drakensjö, MD, PhD student
Ejaz Khushbakht, master student
Patrik Radberger, MD (to be registered in September)

Alumni

Daiana Vasilcanu, MD, PhD, Researcher
Julianna Serly, PhD, Postdoc
Tingting Ling, MD, PhD, Postdoc
Elfar Ulfarsson, MD, PhD student
Eugenio Triay, MD, PhD student
Huiyuan Zheng, PhD student
Natalia Natalishvili, MD, PhD student
Chen Qiu, MD, visiting PhD student
Dan Stefanescu, MD, visiting PhD student
Daniela Nedelcu, visiting PhD student
Tiehong Zhang, visiting PhD student