scispace - formally typeset
Search or ask a question
Author

Michal Kostas

Bio: Michal Kostas is an academic researcher from University of Oslo. The author has contributed to research in topics: Proto-oncogene tyrosine-protein kinase Src & Fibroblast growth factor receptor. The author has an hindex of 7, co-authored 10 publications receiving 148 citations. Previous affiliations of Michal Kostas include Oslo University Hospital & University of Wrocław.

Papers
More filters
Journal ArticleDOI
TL;DR: The relationship between intrinsic stability of FGF proteins and their biological activity for all 18 members of the FGF family is explored, finding the intrinsic ligand instability is an important elementary level of regulation in the F GF signaling system.
Abstract: Fibroblast growth factors (FGFs) deliver extracellular signals that govern many developmental and regenerative processes, but the mechanisms regulating FGF signaling remain incompletely understood. Here, we explored the relationship between intrinsic stability of FGF proteins and their biological activity for all 18 members of the FGF family. We report that FGF1, FGF3, FGF4, FGF6, FGF8, FGF9, FGF10, FGF16, FGF17, FGF18, FGF20, and FGF22 exist as unstable proteins, which are rapidly degraded in cell cultivation media. Biological activity of FGF1, FGF3, FGF4, FGF6, FGF8, FGF10, FGF16, FGF17, and FGF20 is limited by their instability, manifesting as failure to activate FGF receptor signal transduction over long periods of time, and influence specific cell behavior in vitro and in vivo. Stabilization via exogenous heparin binding, introduction of stabilizing mutations or lowering the cell cultivation temperature rescues signaling of unstable FGFs. Thus, the intrinsic ligand instability is an important elementary level of regulation in the FGF signaling system.

49 citations

Journal ArticleDOI
TL;DR: Loss of SHIP2 converted FGF-mediated sustained ERK activation into a transient signal and rescued cell phenotypes triggered by pathologic FGFR-ERK signaling, demonstrating that the adaptor rather than the catalytic activity ofSHIP2 was required.
Abstract: Sustained activation of extracellular signal–regulated kinase (ERK) drives pathologies caused by mutations in fibroblast growth factor receptors (FGFRs) We previously identified the inositol phosphatase SHIP2 (also known as INPPL1) as an FGFR-interacting protein and a target of the tyrosine kinase activities of FGFR1, FGFR3, and FGFR4 We report that loss of SHIP2 converted FGF-mediated sustained ERK activation into a transient signal and rescued cell phenotypes triggered by pathologic FGFR-ERK signaling Mutant forms of SHIP2 lacking phosphoinositide phosphatase activity still associated with FGFRs and did not prevent FGF-induced sustained ERK activation, demonstrating that the adaptor rather than the catalytic activity of SHIP2 was required SHIP2 recruited Src family kinases to the FGFRs, which promoted FGFR-mediated phosphorylation and assembly of protein complexes that relayed signaling to ERK SHIP2 interacted with FGFRs, was phosphorylated by active FGFRs, and promoted FGFR-ERK signaling at the level of phosphorylation of the adaptor FRS2 and recruitment of the tyrosine phosphatase PTPN11 Thus, SHIP2 is an essential component of canonical FGF-FGFR signal transduction and a potential therapeutic target in FGFR-related disorders

41 citations

Journal ArticleDOI
TL;DR: It is shown that osteosarcoma cell lines depleted for PTPRG display increased FGFR activity and are hypersensitive to stimulation by FGF1, andPTPRG may have future clinical relevance by being a predictor of outcome after FGFR inhibitor treatment.

27 citations

Journal ArticleDOI
28 May 2021-Cells
TL;DR: In this paper, the authors review the numerous cellular mechanisms that regulate and turn off FGFR signaling, once the receptor is activated, including endocytosis and endocytic sorting, phosphatase activity, negative regulatory proteins and negative feedback phosphorylation events.
Abstract: FGFR (fibroblast growth factor receptor) signaling controls fundamental processes in embryonic, fetal and adult human life. The magnitude, duration, and location of FGFR signaling must be strictly controlled in order to induce the correct biological response. Uncontrolled receptor signaling has been shown to lead to a variety of diseases, such as skeletal disorders and cancer. Here we review the numerous cellular mechanisms that regulate and turn off FGFR signaling, once the receptor is activated. These mechanisms include endocytosis and endocytic sorting, phosphatase activity, negative regulatory proteins and negative feedback phosphorylation events. The mechanisms act together simultaneously or sequentially, controlling the same or different steps in FGFR signaling. Although more work is needed to fully understand the regulation of FGFR signaling, it is clear that the cells in our body have evolved an extensive repertoire of mechanisms that together keep FGFR signaling tightly controlled and prevent excess FGFR signaling.

22 citations

Journal ArticleDOI
04 Mar 2014-PLOS ONE
TL;DR: It is shown that the nucleolin-FGF1 interaction is critical for the intranuclear phosphorylation of FGF1 by PKCδ and thereby the regulation of nuclear export of F GF1.
Abstract: Extracellular fibroblast growth factor 1 (FGF1) acts through cell surface tyrosine kinase receptors, but FGF1 can also act directly in the cell nucleus, as a result of nuclear import of endogenously produced, non-secreted FGF1 or by transport of extracellular FGF1 via endosomes and cytosol into the nucleus. In the nucleus, FGF1 can be phosphorylated by protein kinase C δ (PKCδ), and this event induces nuclear export of FGF1. To identify intracellular targets of FGF1 we performed affinity pull-down assays and identified nucleolin, a nuclear multifunctional protein, as an interaction partner of FGF1. We confirmed a direct nucleolin-FGF1 interaction by surface plasmon resonance and identified residues of FGF1 involved in the binding to be located within the heparin binding site. To assess the biological role of the nucleolin-FGF1 interaction, we studied the intracellular trafficking of FGF1. In nucleolin depleted cells, exogenous FGF1 was endocytosed and translocated to the cytosol and nucleus, but FGF1 was not phosphorylated by PKCδ or exported from the nucleus. Using FGF1 mutants with reduced binding to nucleolin and a FGF1-phosphomimetic mutant, we showed that the nucleolin-FGF1 interaction is critical for the intranuclear phosphorylation of FGF1 by PKCδ and thereby the regulation of nuclear export of FGF1.

22 citations


Cited by
More filters
Journal ArticleDOI
TL;DR: The mechanisms leading to the deregulation of integrin signaling in cancer and its various consequences are discussed, with emphasis on novel functions, determinants of context dependency, and mechanism-based therapeutic opportunities.

444 citations

01 Jan 2006
TL;DR: In this paper, the importance of mesenchymal-to-epithelial transition (MET) in the formation of clinically significant metastasis was addressed, and it was found that the more metastatic sublines had acquired epithelial characteristics.
Abstract: Epithelial-to-mesenchymal transition (EMT) increases cell migration and invasion, and facilitates metastasis in multiple carcinoma types, but belies epithelial similarities between primary and secondary tumors. This study addresses the importance of mesenchymal-to-epithelial transition (MET) in the formation of clinically significant metastasis. The previously described bladder carcinoma TSU-Pr1 (T24) progression series of cell lines selected in vivo for increasing metastatic ability following systemic seeding was used in this study. It was found that the more metastatic sublines had acquired epithelial characteristics. Epithelial and mesenchymal phenotypes were confirmed in the TSU-Pr1 series by cytoskeletal and morphologic analysis, and by performance in a panel of in vitro assays. Metastatic ability was examined following inoculation at various sites. Epithelial characteristics associated with dramatically increased bone and soft tissue colonization after intracardiac or intratibial injection. In contrast, the more epithelial sublines showed decreased lung metastases following orthotopic inoculation, supporting the concept that EMT is important for the escape of tumor cells from the primary tumor. We confirmed the overexpression of the IIIc subtype of multiple fibroblast growth factor receptors (FGFR) through the TSU-Pr1 series, and targeted abrogation of FGFR2IIIc reversed the MET and associated functionality in this system and increased survival following in vivo inoculation in severe combined immunodeficient mice. This model is the first to specifically model steps of the latter part of the metastatic cascade in isogenic cell lines, and confirms the suspected role of MET in secondary tumor growth.

387 citations

Journal ArticleDOI
TL;DR: G-quadruplex DNA oligonucleotide (AS1411) has been used as a targeting agent to deliver nanoparticles and small molecules into cancer cells as discussed by the authors, but the mechanism underlying the cancer-targeting ability of AS1411 is not completely understood.

209 citations

Journal Article
TL;DR: A better understanding of the mechanisms by which AS1411 targets and kills cancer cells may hasten the development of promising technologies using As1411-linked nanoparticles or conjugates for cancer-targeted therapy and imaging.

165 citations

Journal ArticleDOI
TL;DR: This review presents protein engineering approaches seeking to improve growth factor delivery and efficacy while reducing doses and side effects, and focuses on engineering strategies sought to improve affinity of growth factors for biomaterials or the endogenous extracellular matrix.
Abstract: Growth factors are critical molecules for tissue repair and regeneration. Therefore, recombinant growth factors have raised a lot of hope for regenerative medicine applications. While using growth factors to promote tissue healing has widely shown promising results in pre-clinical settings, their success in the clinic is not a forgone conclusion. Indeed, translation of growth factors is often limited by their short half-life, rapid diffusion from the delivery site, and low cost-effectiveness. Trying to circumvent those limitations by the use of supraphysiological doses has led to serious side-effects in many cases and therefore innovative technologies are required to improve growth factor-based regenerative strategies. In this review, we present protein engineering approaches seeking to improve growth factor delivery and efficacy while reducing doses and side effects. We focus on engineering strategies seeking to improve affinity of growth factors for biomaterials or the endogenous extracellular matrix. Then, we discuss some examples of increasing growth factor stability and bioactivity, and propose new lines of research that the field of growth factor engineering for regenerative medicine may adopt in the future.

113 citations