分枝管狀結構在胚胎發育時期的器官生成中扮演相當重要的角色，目前體外研究分枝管狀構造形成機制的方式，最常用的方式是將Madin-Darby canine kidney (MDCK)腎臟遠端小管細胞培養於三度空間膠原蛋白凝膠內，在肝細胞生長因子(hepatocyte growth factor)誘導下，可形成多細胞分枝管狀構造。除了integrin外，Discoidin domain receptor I (DDR1)為具有tyrosine kinase功能之膠原蛋白纖維接受體。雖然MDCK細胞具有接受體DDR1，然而DDR1在腎臟上皮細胞功能中扮演的角色以及其訊息傳遞仍然尚未釐清。為了探討DDR1的運作功能及其在膠原蛋白纖維中誘導的型態發生之訊息傳遞機制，我們實驗室成功的建立了一些穩定表現wild type或dominant-negative DDR1轉染的MDCK腎上皮細胞株，並將細胞培養於 HGF (2 ng/ml)存在的膠原蛋白凝膠中觀察分枝化腎管的情形。分枝化腎管的形成，其過程需要精細的控制其細胞的附著、移行、分化及細胞生存，我們發現，當細胞培養於HGF存在的膠原蛋白凝膠中時，大量表現 wild type DDR1a或DDR1b的MDCK細胞由於細胞生長及細胞移形受抑制導致其腎管生成及分枝化受到嚴重抑制，而表現dominant negative DDR1之MDCK細胞則由於造成細胞死亡及促進細胞移行，因而抑制了細胞與細胞間結合而亦阻礙了其腎管的形成。大量表現DDR1a或DDR1b的MDCK細胞可增進細胞生存，反之表現dominant negative DDR1造成細胞死亡，此結果顯示DDR1具有調節細胞生存的功能。細胞移行主要由a2b1 integrin正向調節, DDR1a及1b則扮演負向抑制的功能。本研究中顯示DDR1抑制了a2b1 integrin正向調節的Stat1及Stat3活化，進而抑制膠原蛋白纖維所誘導的細胞移行。大量表現DDR1a或DDR1b可同時促進結合SHP-2及SHP-2去磷酸脢活性，進而抑制Stat1及Stat3活化及膠原蛋白纖維所誘導的細胞移行。進一步分析DDR1與SHP-2的結合方式，顯示SHP-2是利用其SH2-SH2 及 PTP domains結合至DDR1的磷酸化位置703及796。利用點突變方式，破壞DDR1的703及796磷酸化位置，會造成其無法行使DDR1的功能在抑制Stat1/3活化、抑制細胞移行以及抑制分枝化腎管的形成。綜合上述結果顯示，DDR1是透過與SHP-2的結合進而調節Stat1/3活化及細胞移行，並影響分枝化腎管的形成。

　Branching tubulogenesis is an important feature of many organs during embryonic development. Madin-Darby canine kidney (MDCK) cells develop branching tubules in three-dimensional collagen gel in the induction of hepatocyte growth factor (HGF). Discoidin domain receptor I (DDR1) is a receptor tyrosine kinase and serves as the receptor for collagen in addition to integrins. MDCK cells normally express DDR1. However, the function of DDR1 in this in vitro model system has not been understood. To dissect the function of DDR1, we established stable-transfected MDCK cells that harbored DDR1a, DDR1b or dominant-negative DDR1, and cultured these transfectants in collagen gel with HGF to analyze for changes in branching morphogenesis. Tubulogenesis is a functional result of cell proliferation, migration, and cell survival. Overexpression of DDR1a or DDR1b inhibited the cell proliferation and collagen-induced cell migration, which in turn suppressed HGF-induced branching tubulogenesis. In contrast, dominant-negative DDR1 could enhance apoptosis and cell migration, which resulted in disruption of tubule structure and developing mostly cell aggregates with multiple long extended processes. Overexpression of DDR1a or 1b in MDCK cells decreased cell apoptosis on collagen gel, whereas dominant-negative DDR1 enhanced cell apoptosis, suggesting that the DDR1 functions in maintaining cell survival. Collagen-induced cell migration is mainly triggered by a2b1 integrin, whereas DDR1a and 1b may serve as a negative regulator for a2b1 integrin during migration. Here, we showed that DDR1 downregulated collagen-induced tyrosine phosphorylation of Signal transducers and activators of transcription (Stat) 1/3 and cell migration triggered by a2b1 integrin. Overexpression of DDR1 increased the binding DDR1a/b to Src-homology-2 (SH2)-domain-containing protein 2 (SHP-2) and upregulated the tyrosine phosphatase activity of SHP-2, which sequentially suppressed the activation of Stat1/3 and cell migration. We demonstrated that the tandem Src-homology-2 (SH2) and Phosphotyrosyl phosphatases (PTP) domains of SHP-2 were responsible for interaction with DDR1, and that both tyrosine phosphorylation sites 703 and 796 of DDR1 were essential for this interaction. Mutation of tyrosine 703 or 796 of DDR1 abolished the ability of DDR1 to inhibit the tyrosine phosphorylation of Stat1/3, restored collagen-induced cell migration and the HGF-induced branching tubulogenesis. These results indicate that SHP-2 mediates the DDR1-suppressed of Stat1/3 activation and cell migration, as well as the HGF-induced branching tubulogenesis in collagen gel.

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