APPL endosomes are not obligatory endocytic intermediates but act as stable cargo-sorting compartments

Kalaidzidis, Inna V; Miączyńska, Marta; Brewińska-Olchowik, Marta; Hupalowska, Anna; Ferguson, Charles; Parton, Robert G.; Kalaidzidis, Yannis; Zerial, Marino

doi:10.1083/jcb.201311117

Cited by 88 publications

(145 citation statements)

References 67 publications

Supporting

Mentioning

126

Contrasting

Order By: Relevance

“…S4C). In agreement with this interpretation, APPL1 has been recently described as an important factor for bidirectional sorting of endosomal cargo that is destined for plasma membrane delivery or for endocytic processing (Kalaidzidis et al, 2015). Finally, as a corollary to the study of APPL1 and PI3K signaling for LTP, we have found that inhibitors of the immediate downstream effectors of this pathway, PDK1 and Akt, do not affect synaptic potentiation.…”

Section: Discussionsupporting

confidence: 64%

APPL1 gates long-term potentiation through its plekstrin homology domain

Fernández‐Monreal

Sánchez‐Castillo

Esteban

2016

Journal of Cell Science

View full text Add to dashboard Cite

Hippocampal synaptic plasticity involves both membrane trafficking events and intracellular signaling, but how these are coordinated is far from clear. The endosomal transport of glutamate receptors in and out of the postsynaptic membrane responds to multiple signaling cascades triggered by synaptic activity. In this work, we have identified adaptor protein containing a plekstrin homology domain, phosphotyrosine-binding domain and leucine zipper motif 1 (APPL1) as a crucial element linking trafficking and signaling during synaptic plasticity. We show that APPL1 knockdown specifically impairs PI3K-dependent forms of synaptic plasticity, such as long-term potentiation (LTP) and metabotropic-glutamate-receptor-dependent long-term depression (mGluR-LTD). Indeed, we demonstrate that APPL1 is required for the activation of the phosphatidylinositol triphosphate (PIP 3 ) pathway in response to LTP induction. This requirement can be bypassed by membrane localization of PI3K and is related to phosphoinositide binding. Interestingly, inhibitors of PDK1 (also known as PDPK1) and Akt have no effect on LTP expression. Therefore, we conclude that APPL1 gates PI3K activation at the plasma membrane upon LTP induction, which is then relayed by downstream PIP 3 effectors that are different from PDK1 and Akt.

show abstract

Section: Discussionsupporting

confidence: 64%

APPL1 gates long-term potentiation through its plekstrin homology domain

Fernández‐Monreal

Sánchez‐Castillo

Esteban

2016

Journal of Cell Science

View full text Add to dashboard Cite

show abstract

“…These data point to a positive feedback loop resulting from the crosstalk between signaling and early endocytic trafficking and impinging on Dyn1 activity. APPL1, a Rab5 effector, labels a sub-population of Rab5-positive signaling and sorting endosomes that can be regulated by EGFR through Grb2 (Kalaidzidis et al, 2015; Martinu et al, 2002; Miaczynska et al, 2004; Schenck et al, 2008). Grb2 interacts with dynamin’s proline/arginine-rich domain (Solomaha et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Crosstalk between CLCb/Dyn1-Mediated Adaptive Clathrin-Mediated Endocytosis and Epidermal Growth Factor Receptor Signaling Increases Metastasis

et al. 2017

View full text Add to dashboard Cite

SUMMARY Signaling receptors are internalized and regulated by clathrin-mediated endocytosis (CME). Two clathrin light chain isoforms, CLCa and CLCb, are integral components of the endocytic machinery whose differential functions remain unknown. We report that CLCb is specifically upregulated in non-small-cell lung cancer (NSCLC) cells and is associated with poor patient prognosis. Engineered single CLCb-expressing NSCLC cells, as well as “switched” cells that predominantly express CLCb, exhibit increased rates of CME and altered clathrin-coated pit dynamics. This “adaptive CME” resulted from upregulation of dynamin-1 (Dyn1) and its activation through a positive feedback loop involving enhanced epidermal growth factor (EGF)-dependent Akt/GSK3β phosphorylation. CLCb/Dyn1-dependent adaptive CME selectively altered EGF receptor trafficking, enhanced cell migration in vitro, and increased the metastatic efficiency of NSCLC cells in vivo. We define molecular mechanisms for adaptive CME in cancer cells and a role for the reciprocal crosstalk between signaling and CME in cancer progression.

show abstract

“…Endosomal sorting could be more complex requiring several signaling molecules like phosphatidylinositol 3-kinase (36), receptor tyrosine kinase (37), and various effectors. Recent studies have shown that APPL1, a Rab5 effector, regulates the differential sorting of EGF and transferrin from endosomes (38). Moreover, cargo sorting might occur at the plasma membrane depending on the mode of entry as clathrin-coated vesicles are also differentially tethered to the two types of endosomes (39).…”

Section: Discussionmentioning

confidence: 99%

Rab5 Isoforms Specifically Regulate Different Modes of Endocytosis in Leishmania

Rastogi

Verma

Kapoor

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

Differential functions of Rab5 isoforms in endocytosis are not well characterized. Here, we cloned, expressed, and characterized Rab5a and Rab5b from Leishmania and found that both of them are localized in the early endosome. To understand the role of LdRab5 isoforms in different modes of endocytosis in Leishmania, we generated transgenic parasites overexpressing LdRab5a, LdRab5b, or their dominant-positive (LdRab5a:Q93L and LdRab5b:Q80L) or dominant-negative mutants (LdRab5a: N146I and LdRab5b:N133I). Using LdRab5a or its mutants overexpressing parasites, we found that LdRab5a specifically regulates the fluid-phase endocytosis of horseradish peroxidase and also specifically induced the transport of dextran-Texas Red to the lysosomes. In contrast, cells overexpressing LdRab5b or its mutants showed that LdRab5b explicitly controls receptormediated endocytosis of hemoglobin, and overexpression of LdRab5b:WT enhanced the transport of internalized Hb to the lysosomes in comparison with control cells. To unequivocally demonstrate the role of Rab5 isoforms in endocytosis in Leishmania, we tried to generate null-mutants of LdRab5a and LdRab5b parasites, but both were lethal indicating their essential functions in parasites. Therefore, we used heterozygous LdRab5a ؉/؊ and LdRab5b ؉/؊ cells. LdRab5a ؉/؊ Leishmania showed 50% inhibition of HRP uptake, but hemoglobin endocytosis was uninterrupted. In contrast, about 50% inhibition of Hb endocytosis was observed in LdRab5b ؉/؊ cells without any significant effect on HRP uptake. Finally, we tried to identify putative LdRab5a and LdRab5b effectors. We found that LdRab5b interacts with clathrin heavy chain and hemoglobin receptor. However, LdRab5a failed to interact with the clathrin heavy chain, and interaction with hemoglobin receptor was significantly less. Thus, our results showed that LdRab5a and LdRab5b differentially regulate fluid phase and receptor-mediated endocytosis in Leishmania.

show abstract

APPL endosomes are not obligatory endocytic intermediates but act as stable cargo-sorting compartments

Cited by 88 publications

References 67 publications

APPL1 gates long-term potentiation through its plekstrin homology domain

APPL1 gates long-term potentiation through its plekstrin homology domain

Crosstalk between CLCb/Dyn1-Mediated Adaptive Clathrin-Mediated Endocytosis and Epidermal Growth Factor Receptor Signaling Increases Metastasis

Rab5 Isoforms Specifically Regulate Different Modes of Endocytosis in Leishmania

Contact Info

Product

Resources

About