Fine tuning of growth factor signals depends on fibrillin microfibril networks.
Growth factors, potent regulators of cell differentiation, tissue morphogenesis, tissue homeostasis, and cellular response to injury, reside in the extracellular matrix. Genetic evidence in humans and mice as well as biochemical data implicate fibrillins and LTBPs in the extracellular control of TGFbeta and BMP signaling. Fibrillins and LTBPs form tissue-specific and temporally regulated microfibril networks. In the developing embryo, three fibrillins and four LTBPs contribute molecular heterogeneity to microfibril networks, and provide different templates upon which TGFbeta-related growth factors can be positioned. By accommodating this molecular heterogeneity, microfibril architecture can orchestrate a variety of different signals in very specific tissue locations. Human fibrillinopathies display a broad phenotypic spectrum from tall to short stature, from hypermobile joints to joint contractures and stiffness, and from severe to mild or no cardiovascular manifestations. A spectrum of growth factor dysregulation may be caused by differential effects of mutations in fibrillins on microfibril architecture, thus altering appropriate targeting or positioning of growth factors within microfibril networks. Growth factor dysregulation may help to explain the broad phenotypic spectrum of the fibrillinopathies.
Charbonneau
Noe L
NL
Shriners Hospital for Children, and the Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, Oregon.
Ono
Robert N
RN
Corson
Glen M
GM
Keene
Douglas R
DR
Sakai
Lynn Y
LY
D000595:Amino Acid Sequence; D000818:Animals; D005109:Extracellular Matrix / Q000737:chemistry*; D000071837:Fibrillins; D006133:Growth Substances / Q000502:physiology*; D006801:Humans; D020894:Microfibrils / Q000502:physiology*; D008840:Microfilament Proteins / Q000502:physiology*; D008969:Molecular Sequence Data; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction
D000071837:Fibrillins; D006133:Growth Substances; D008840:Microfilament Proteins