APPL Proteins Link Rab5 to Nuclear Signal Transduction via an Endosomal Compartment

Miączyńska, Marta; Christoforidis, Savvas; Giner, Angelika; Shevchenko, Anna; Uttenweiler-Joseph, Sandrine; Habermann, Bianca; Wilm, Matthias; Parton, Robert G.; Zerial, Marino

doi:10.1016/s0092-8674(04)00117-5

Cited by 511 publications

(668 citation statements)

References 60 publications

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“…4A) and HA-tagged wild type OCRL (Fig. 4B), accumulated on the enlarged endosomes induced by transfection of constitutively active Rab5 (Rab5Q79L) as reported previously [11,14,18]. OCRL G664D, i.e.…”

Section: Independent Roles Of Appl1 and Rab5 In The Localization Of Ocrlsupporting

confidence: 83%

All known patient mutations in the ASH-RhoGAP domains of OCRL affect targeting and APPL1 binding

McCrea

Paradise

Tomasini

et al. 2008

Biochemical and Biophysical Research Communications

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Mutations in the inositol 5-phosphatase OCRL are responsible for Lowe syndrome, an X-linked disorder characterized by bilateral cataracts, mental retardation, neonatal hypotonia, and renal Fanconi syndrome, and for Dent disease, another X-linked condition characterized by kidney reabsorption defects. We have previously described an interaction of OCRL with the endocytic adaptor APPL1 that links OCRL to protein networks involved in the disease phenotype. Here we provide new evidence showing that among the interactions which target OCRL to membranes of the endocytic pathway, binding to APPL1 is the only one abolished by all known disease-causing missense mutations in the ASH-RhoGAP domains of the protein. Furthermore, we demonstrate that APPL1 and rab5 independently contribute to recruit OCRL to enlarged endosomes induced by the expression of constitutively active Rab5. Thus, binding to APPL1 helps localize OCRL at specific cellular sites, and disruption of this interaction may play a role in disease.

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Section: Independent Roles Of Appl1 and Rab5 In The Localization Of Ocrlsupporting

confidence: 83%

All known patient mutations in the ASH-RhoGAP domains of OCRL affect targeting and APPL1 binding

McCrea

Paradise

Tomasini

et al. 2008

Biochemical and Biophysical Research Communications

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“…The association of macropinosomes with EEA1 was less prominent than with Rab5 reaching a maximum of 8.0%. That this Rab5 effector and tethering factor is only found on a subset of EEs 43, 57 may explain the low level of colocalization we observed. Perhaps, early macropinosomes, such as classical endosomes, exist as several distinct subsets.…”

Section: Discussionmentioning

confidence: 60%

“…We noted that the colocalization of virus with EEA1 was lower than Rab5a. This could be due to the fact that EEA1 is only found on a subset of early macropinosomes, as is the case with classical EEs 43. As EEA1 is required for docking and homotypic fusion of early macropinosomes 20, another possibility is that fusion of virus‐containing vacuoles is a rapid event and thus the association of EEA1 with VACV‐containing macropinosomes is brief.…”

Section: Resultsmentioning

confidence: 99%

Vaccinia Virus Infection Requires Maturation of Macropinosomes

Rizopoulos

Balistreri

Kilcher

et al. 2015

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The prototypic poxvirus, vaccinia virus (VACV), occurs in two infectious forms, mature virions (MVs) and extracellular virions (EVs). Both enter HeLa cells by inducing macropinocytic uptake. Using confocal microscopy, live‐cell imaging, targeted RNAi screening and perturbants of endosome maturation, we analyzed the properties and maturation pathway of the macropinocytic vacuoles containing VACV MVs in HeLa cells. The vacuoles first acquired markers of early endosomes [Rab5, early endosome antigen 1 and phosphatidylinositol(3)P]. Prior to release of virus cores into the cytoplasm, they contained markers of late endosomes and lysosomes (Rab7a, lysosome‐associated membrane protein 1 and sorting nexin 3). RNAi screening of endocytic cell factors emphasized the importance of late compartments for VACV infection. Follow‐up perturbation analysis showed that infection required Rab7a and PIKfyve, confirming that VACV is a late‐penetrating virus dependent on macropinosome maturation. VACV EV infection was inhibited by depletion of many of the same factors, indicating that both infectious particle forms share the need for late vacuolar conditions for penetration.

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“…28 In addition, the interaction of APPL1 with epidermal growth factor induces translocation of the linker protein to the nucleus, where it associates with a chromatin-remodeling complex that regulates transcription. 73 It is reasonable that interactions of APPL1 with adiponectin, FSH and insulin receptors may precipitate a similar signaling process, although no data yet exist to confirm this assumption. Figure 1 depicts the known and assumed pathways for the transduction of the adiponectin signal in ovarian granulosa cells.…”

Section: Mechanisms Of Action Of Adiponectin In Reproductive Tissuesmentioning

confidence: 99%

The ‘beneficial’ adipokines in reproduction and fertility

et al. 2007

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The objective of this study was to review the available information on the signaling proteins produced by adipose tissue in the context of their role in regulating reproductive processes, including ovarian and uterine function. It is well known that both obesity and excessive leanness are associated with reproductive dysfunction. Adipokines are cytokines predominately or exclusively expressed by adipose tissue that circulate and affect target tissues. Four known adipokines, adiponectin, visfatin/ PBEF, omentin and vaspin, all increase tissue sensitivity to insulin, and are thus described as 'beneficial'. There is strong support for a role for adiponectin in the function of the ovary and placenta. There is evidence for direct effects of this adipokine on the late stages of folliculogenesis, and additive interactions of adiponectin with insulin and gonadotropins in inducing periovulatory changes in ovarian follicles. In addition, clinical and genomic studies associate hypoadiponectinemia with obesity-related reproductive disorders, including the polycystic ovarian syndrome. The roles for visfatin/PBEF, omentin and vaspin in reproduction remain to be established. The conclusion thus drawn is that the expression of insulin-sensitizing adipokines varies with adipose abundance. These adipokines have demonstrated both the potential effects on ovarian function and the possible effects on the formation of the placenta, acting through multiple mechanisms.

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APPL Proteins Link Rab5 to Nuclear Signal Transduction via an Endosomal Compartment

Cited by 511 publications

References 60 publications

All known patient mutations in the ASH-RhoGAP domains of OCRL affect targeting and APPL1 binding

All known patient mutations in the ASH-RhoGAP domains of OCRL affect targeting and APPL1 binding

Vaccinia Virus Infection Requires Maturation of Macropinosomes

The ‘beneficial’ adipokines in reproduction and fertility

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