Epithelial-mesenchymal transition (EMT) describes the differentiation (Fig. 1). EMT is therefore envisioned as a differentiation or morphogenetic process in which new tissue types are generated during embryogenesis, and which contributes to the pathogenesis of disease, such as metastatic cancer and tissue fibrosis.(2-5) The inverse process of mesenchymalepithelial transition (MET) describes how transitory mesenchymal cells generate polarized epithelia after migration and homing into new sites of tissue formation (Fig. 1). MET has been described in the context of embryonic development and is also perturbed pathologically in fibrotic disorders.(5) Morphogenetic processes such as EMT or MET are guided by the functional interplay of many signal transduction pathways, usually initiated by secreted polypeptide factors, which aim at regulating a new set of transcriptional and post-translational events, leading to the generation of new cellular phenotypes. Here, we discuss the role of different pathways in the control of EMT during embryogenesis and in disease. EMT is important during embryogenesisDuring the early stages of embryogenesis, the three germ layers, ectoderm, mesoderm and endoderm, form via an ontogenetic process called gastrulation (which stands for gut formation). While gastrulation in lower chordates involves movements of epithelial cell sheets, (6) in higher vertebrates, the same process evolved a dependency on EMT, which leads to the formation of migratory mesenchyme that progresses along the primitive streak and populates new areas of the embryo that will develop into mesoderm and endoderm.(1) Fibroblast growth factor (FGF) signaling via receptor tyrosine kinases (RTK) promotes mesodermal formation and mesenchymal cell migration through the primitive streak.(7) An important target of FGF signaling during gastrulation is the master regulator of EMT, Snail, which directly represses expression of the epithelial integral component of adherens junctions, E-cadherin.(7 -9) Furthermore, Wnt signaling via β-catenin and its nuclear partner LEF-1 is implicated in the EMT process during gastrulation, and stabilization of β-catenin accelerates the emergence of premature EMT in the ectoderm. (10,11) At a later stage of embryogenesis, epithelial cells from the neural tube in the dorsal side of the embryo, the neural crest, undergo EMT, and the mesenchymal cells produced often migrate long distances to new tissue areas, in order to differentiate into several new mesenchymal cell types such as somites, bone and chondrocytes.(6) Neural crest EMT is regulated by dosedependent actions of bone morphogenetic proteins (BMP), which are members of the transforming growth factor (TGF)-β superfamily, and a cohort of transcription factors, including paired-box, high-mobility group (HMG), winged-helix transcription factors and Snail. (12) In addition to neural crest EMT, members of the TGF-β superfamily cause palatal EMT in the mouse in order to create the connective tissue across the palate. (13) This action is mainly attributed...

No abstract

This study systematically analyzes platelet-derived growth factor (PDGF) receptor expression in six types of common tumors as well as examines associations between PDGF ␤-receptor status and clinicopathological characteristics in breast cancer. PDGF receptor expression was determined by immunohistochemistry on tumor tissue microarrays. Breast tumor data were combined with prognostic factors and related to outcome endpoints. PDGF ␣-and ␤-receptors were independently expressed, at variable frequencies, in the tumor stroma of all tested tumor types. There was a significant association between PDGF ␤-receptor expression on fibroblasts and perivascular cells in individual colon and prostate tumors. In breast cancer, high stromal PDGF ␤-receptor expression was significantly associated with high histopathological grade, estrogen receptor negativity, and high HER2 expression. High stromal PDGF ␤-receptor expression was correlated with significantly shorter recurrence-free and breast cancer-specific survival. The prognostic significance of stromal PDGF ␤-receptor expression was particularly prominent in tumors from premenopausal women. Stromal PDGF ␣-and ␤-receptor expression is a common, but variable and independent, property of solid tumors. In breast cancer, stromal PDGF ␤-receptor expression significantly correlates with less favorable clinicopatho-

The ubiquitin (Ub) ligase Cbl plays a critical role in attenuation of receptor tyrosine kinase (RTK) signaling by inducing ubiquitination of RTKs and promoting their sorting for endosomal degradation. Herein, we describe the identification of two novel Cbl-interacting proteins, p70 and Clip4 (recently assigned the names Sts-1 and Sts-2, respectively), that inhibit endocytosis of epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor. Sts-1 and Sts-2 contain SH3 domains that interacted with Cbl, Ub-associated domains, which bound directly to mono-Ub or to the EGFR/Ub chimera as well as phosphoglycerate mutase domains that mediated oligomerization of Sts-1/2. Ligand-induced recruitment of Sts-1/Sts-2 into activated EGFR complexes led to inhibition of receptor internalization, reduction in the number of EGFR-containing endocytic vesicles, and subsequent block of receptor degradation followed by prolonged activation of mitogenic signaling pathways. On the other hand, interference with Sts-1/ Sts-2 functions diminished ligand-induced receptor degradation, cell proliferation, and oncogenic transformation in cultured fibroblasts. We suggest that Sts-1 and Sts-2 represent a novel class of Ub-binding proteins that regulate RTK endocytosis and control growth factorinduced cellular functions.

The relationship between platelet‐derived growth factor (PDGF) and the proto‐oncogene c‐sis has been determined by amino acid sequence analysis of PDGF and nucleotide sequence analysis of c‐sis genomic clones. The nucleotide sequences of five regions of the human c‐sis gene which are homologous to sequences of the transforming region (v‐sis) of simian sarcoma virus (SSV) were determined. By alignment of the c‐sis and v‐sis nucleotide sequences the predicted amino acid sequence of a polypeptide homologous to the putative transforming protein p28sis of SSV was deduced. Both predicted sequences use the same termination codon and additional coding sequences may lie 5′ to the homologous regions. Amino acid sequence analysis of the PDGF B chain shows identity to the amino acid sequence predicted from the c‐sis sequences over 109 amino acid residues. Polymorphism may exist at two amino acid residues. These results suggest that c‐sis encodes a polypeptide precursor of the B chain. A partial amino acid sequence of the PDGF A chain is also described. This chain is 60% homologous to the B chain and cannot be encoded by that part of c‐sis which has been sequenced but could be encoded by sequences which lie 5′ to the five regions of v‐sis homology in c‐sis, or at a separate locus.