title: Appl1 and Appl2 are Expendable for Mouse Development But Are Essential for HGF-Induced Akt Activation and Migration in Mouse Embryonic Fibroblasts.
abstract: Although Appl1 and Appl2 have been implicated in multiple cellular activities, we and others have found that Appl1 is dispensable for mouse embryonic development, suggesting that Appl2 can substitute for Appl1 during development. To address this possibility, we generated conditionally targeted Appl2 mice. We found that ubiquitous Appl2 knockout (Appl2-/-) mice, much like Appl1-/- mice, are viable and grow normally to adulthood. Intriguingly, when Appl1-/- mice were crossed with Appl2-/- mice, we found that homozygous Appl1;Appl2 double knockout (DKO) animals are also viable and grossly normal with regard to reproductive potential and postnatal growth. Appl2-null and DKO mice were found to exhibit altered red blood cell physiology, with erythrocytes from these mice generally being larger and having a more irregular shape than erythrocytes from wild type mice. Although Appl1/2 proteins have been previously shown to have a very strong interaction with phosphatidylinositol-3 kinase (Pi3k) in thymic T cells, Pi3k-Akt signaling and cellular differentiation was unaltered in thymocytes from Appl1;Appl2 (DKO) mice. However, Appl1/2-null mouse embryonic fibroblasts exhibited defects in HGF-induced Akt activation, migration, and invasion. Taken together, these data suggest that Appl1 and Appl2 are required for robust HGF cell signaling but are dispensable for embryonic development and reproduction.
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Yinfei
authors.initials: Y
authors.lastname: Tan
authors.affiliation: Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas.
authors.forename: Xiaoban
authors.initials: X
authors.lastname: Xin
authors.affiliation: Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Coffey
authors.affiliation: Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: David L
authors.initials: DL
authors.lastname: Wiest
authors.affiliation: Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas.
authors.forename: Lily Q
authors.initials: LQ
authors.lastname: Dong
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Testa
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000378:metabolism*; D000483:Alleles; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D004622:Embryo, Mammalian / Q000166:cytology; D047108:Embryonic Development / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018390:Gene Targeting; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D000066450:Mouse Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D038081:Organogenesis / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012098:Reproduction; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C510733:Appl1 protein, mouse; C000602283:DCC-interacting protein 13-beta, mouse; D017228:Hepatocyte Growth Factor; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt