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Daniel RifkinProfessor, Department of Cell Biology
Charles Aden Poindexter Professor of Medicine, Department of Medicine
Dir Cell& MoleBio Pgm Instrc& Lecturer-Cell Bio
550 First Avenue
New York, NY 10016
Research SummaryThe Rifkin lab's major interest is in understanding transfer of information in the extracellular environment and the impact of this process on diseases such as cancer. As a model to study how extracellular molecular cues are processed, we have chosen to examine the manner in which growth factors are presented to their receptors. While at first thought this may appear to be straight forward, the interaction of a growth factor with its receptor occurs only under specific conditions: growth factor diffusion must be controlled to ensure that sufficiently high concentrations are reached, many growth factors must be activated before binding to their cognate receptor, and growth factors function is highly contextual. These facts make the problem of understanding growth factor availability in both time and space interesting and challenging. Indeed, improper growth factor presentation may be the cause of a number of pathologies including tumor growth, fibrosis, and autoimmunity.
Our research is focused on elucidating how transforming growth factor-ß (TGF-ß) is regulated. The TGF-ßs (ß1, ß2, ß3) are 25kD dimeric cytokines derived from larger precursors by intracellular processing by furins. However, even though the bonds between the TGF-ß dimer and the propeptide dimer are cleaved within the trans Golgi, the propeptide remains tightly associated with the growth factor by non covalent interactions. This association renders the TGF-ß unable to interact with its receptor. Thus, TGF-ß is normally secreted in a latent form and to act must be liberated from interaction with its propeptide, also known as the latency associated protein (LAP). The extracellular forms of latent TGF-ß are also associated with a second gene product, the latent TGF-ß binding protein (LTBP). LTBPs are complex proteins consisting of multiple EGF-like domains and signature 8-cysteine-containing modules. LTBPs are joined to LAP via a pair of disulfide bonds that form between cysteine residues near the amino terminus of LAP and a pair of cysteines in the third 8-cysteine domains of LTBP-1, 3 or 4
The research efforts of the laboratory are focused on several themes that relate to the fundamental biology of TGF-ß and its activation. First, we are interested in elucidating the mechanisms that convert latent to active TGF-ß. We have described activation by proteases and by the integrin alpha vß6. We are currently performing molecular experiments to establish the role of LTBP in this process, the regions of LTBP that are involved, and the biochemical constituents that are part of the activation reaction. We have also developed a genetic screen for molecules that activate latent TGF-ß. We have isolated several cell clones that may express novel activators and are in the process of characterizing these activators. Our ultimate goal is to understand latent TGF-ß activation in a way that will permit the design of inhibitors for specific activation pathways.
Second, we are studying LTBP function by creating mouse mutants in which either null mutations have been introduced into the LTBP genes, mutations have been made that affect LTBP function, or point mutations in LAP have been generated that will block binding to LTBP. These mutations have revealed several interesting phenotypes in bone, lung, and fat differentiation are informative with respect to aspects of TGF-ß biology.
Third, we are interested in the role of the LTBPs during early development. We have found that these proteins may participate in patterning of the dorsal ventral axes in early embryos. We think that this occurs via interactions with the TGF-ß superfamily members activin and nodal. We are interested in understanding the developmental consequences of these interactions as well as the biochemical parameters that control them.
Research InterestsExtracellular Control of Growth Factor Action
Regulation of the Bioavailability of TGF-beta and TGF-beta-Related Proteins
Robertson, Ian B; Rifkin, Daniel B. Regulation of the Bioavailability of TGF-beta and TGF-beta-Related Proteins. Cold Spring Harbor perspectives in biology. 2016 Jun 1;8(6):?-? (2124892)
Isolation and cytokine analysis of lamina propria lymphocytes from mucosal biopsies of the human colon
Bowcutt, Rowann; Malter, Lisa B; Chen, Lea Ann; Wolff, Martin J; Robertson, Ian; Rifkin, Daniel B; Poles, Michael; Cho, Ilseug; Loke, P'ng. Isolation and cytokine analysis of lamina propria lymphocytes from mucosal biopsies of the human colon. Journal of immunological methods. 2015 Mar 10;421:27-35 e0003566 (1495252)
Function of Latent TGFbeta Binding Protein 4 and Fibulin 5 in Elastogenesis and Lung Development
Dabovic, Branka; Robertson, Ian B; Zilberberg, Lior; Vassallo, Melinda; Davis, Elaine C; Rifkin, Daniel B. Function of Latent TGFbeta Binding Protein 4 and Fibulin 5 in Elastogenesis and Lung Development. Journal of cellular physiology. 2015 Jan ;230(1):226-236 (1283392)
L(59) TGF-beta LAP degradation products serve as a promising blood biomarker for liver fibrogenesis in mice
Hara, Mitsuko; Inoue, Ikuyo; Yamazaki, Yuta; Kirita, Akiko; Matsuura, Tomokazu; Friedman, Scott L; Rifkin, Daniel B; Kojima, Soichi. L(59) TGF-beta LAP degradation products serve as a promising blood biomarker for liver fibrogenesis in mice. Fibrogenesis & tissue repair. 2015 Sep 15;8:17-17 (1779352)
Abrogation of both short and long forms of latent transforming growth factor-beta binding protein-1 causes defective cardiovascular development and is perinatally lethal
Horiguchi, Masahito; Todorovic, Vesna; Hadjiolova, Krassimira; Weiskirchen, Ralf; Rifkin, Daniel B. Abrogation of both short and long forms of latent transforming growth factor-beta binding protein-1 causes defective cardiovascular development and is perinatally lethal. Matrix biology. 2015 Mar 21;43:61-70 (1602602)