A novel dileucine lysosomal-sorting-signal mediates intracellular EGF-receptor retention independently of protein ubiquitylation

Tsacoumango, Amy; Kil, Song Jae; Ma, Ligeng; Sönnichsen, Frank D.; Carlin, Cathleen R.

doi:10.1242/jcs.02527

Cited by 20 publications

(22 citation statements)

References 83 publications

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“…It has been documented that GGAs display a critical function in packaging of mannose-6-phosphate receptors into clathrin-coated vesicls in the TGN, which could be regulated by the phosphorylation state of GGAs (131, 186, 189). Thus, to ascertain the function of dileucine-based signals in relation to [D/E]XXXL [L/I] or DXXXL motifs, it should be emphasized that the former are recognized by heterotetrameric adaptor complexes such as AP-1, AP-2, AP-3, and AP-4, which later bind GGA adaptor proteins (4, 147, 148, 190–192). …”

Section: Modulation Of Receptor Trafficking and Sequestration By Smentioning

confidence: 99%

Functional roles of short sequence motifs in the endocytosis of membrane receptors

Pandey¹

2009

Front Biosci

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Internalization and trafficking of cell-surface membrane receptors and proteins into subcellular compartments is mediated by specific short-sequence signal motifs, which are usually located within the cytoplasmic domains of these receptor and protein molecules. The signals usually consist of short linear amino acid sequences, which are recognized by adaptor coat proteins along the endocytic and sorting pathways. The complex arrays of signals and recognition proteins ensure the dynamic movement, accurate trafficking, and designated distribution of transmembrane receptors and ligands into intracellular compartments, particularly to the endosomal-lysosomal system. This review summarizes the new information and concepts, integrating them with the current and established views of endocytosis, intracellular trafficking, and sorting of membrane receptors and proteins. Particular emphasis has been given to the functional roles of short-sequence signal motifs responsible for the itinerary and destination of membrane receptors and proteins moving into the subcellular compartments. The specific characteristics and functions of short-sequence motifs, including various tyrosine-based, dileucine-type, and other short-sequence signals in the trafficking and sorting of membrane receptors and membrane proteins are presented and discussed.

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Section: Modulation Of Receptor Trafficking and Sequestration By Smentioning

confidence: 99%

Functional roles of short sequence motifs in the endocytosis of membrane receptors

Pandey¹

2009

Front Biosci

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“…Interestingly, 87-LL is part of a larger motif that is precisely conserved in the EGFR (26), suggesting its involvement in cargo selection and/or targeting EGFRs to lysosomes. This conjecture is supported by evidence that this sequence in the EGFR is necessary for ligand-induced trafficking to lysosomes (32,33) and also RID␣-mediated diversion of recycling EGFRs to lysosomes (44). Thus, although 87-LL may not be directly involved in AP recognition, it undoubtedly has an important role in RID␣ function at least as it relates to EGFR downregulation.…”

Section: Discussionmentioning

confidence: 92%

A Tyrosine-Based Signal Plays a Critical Role in the Targeting and Function of Adenovirus RIDα Protein

Cianciola¹,

Crooks²,

Shah³

et al. 2007

J Virol

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Early region 3 genes of human adenoviruses contribute to the virus life cycle by altering the trafficking of cellular proteins involved in adaptive immunity and inflammatory responses. The ability of early region 3 genes to target specific molecules suggests that they could be used to curtail pathological processes associated with these molecules and treat human disease. However, this approach requires genetic dissection of the multiple functions attributed to early region 3 genes. The purpose of this study was to determine the role of targeting on the ability of the early region 3-encoded protein RID␣ to downregulate the EGF receptor. A fusion protein between the RID␣ cytoplasmic tail and glutathione S-transferase was used to isolate clathrin-associated adaptor 1 and adaptor 2 protein complexes from mammalian cells. Deletion and site-directed mutagenesis studies showed that residues 71-AYLRH of RID␣ are necessary for in vitro binding to both adaptor complexes and that Tyr72 has an important role in these interactions. In addition, RID␣ containing a Y72A point mutation accumulates in the trans-Golgi network and fails to downregulate the EGF receptor when it is introduced into mammalian cells as a transgene. Altogether, our data suggest a model where RID␣ is trafficked directly from the trans-Golgi network to an endosomal compartment, where it intercepts EGF receptors undergoing constitutive recycling to the plasma membrane and redirects them to lysosomes.Adenoviruses (Ads) are nonenveloped DNA viruses that replicate and assemble in the host cell nucleus (13). Ads are responsible for approximately 5% of acute upper respiratory tract (3) and 15% of lower respiratory tract (1) infections in infants and children. Similar to other DNA viruses, Ads are also capable of establishing persistent infections, because they have evolved numerous strategies to evade host antiviral surveillance mechanisms. Some of these same mechanisms also facilitate survival of the virus during an acute infection. Thus, a thorough understanding of viral genes that control host immune and inflammatory responses is fundamental to our ability to prevent and treat virus-induced disease at multiple levels. These mechanisms have also influenced strategies for designing Ad-based vectors for gene therapy (14).The early region 3 (E3) transcription genes of human Ads encode several proteins that exploit the intracellular trafficking machinery to modify host immune or inflammatory responses (11, 29). Thus, E3 proteins have served as novel probes of membrane transport mechanisms in addition to providing insights to Ad pathophysiology. The most abundant E3 protein, E3/19K, suppresses the host adaptive immunity response by retaining class I MHC molecules in the endoplasmic reticulum. Other E3 proteins affect the functions of molecules involved in proliferation and apoptosis, intracellular cell signaling events linked to NF-B, and secretion of proinflammatory chemokines. Two E3 proteins, RID␣ (also called E3-10.4 and E3-13.7) and RID␤ (also called E3-14.5),...

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“…Stable NR6 cell lines expressing human wild-type EGFRs or receptors with 679-LL converted to 679-AA are described elsewhere (Kil et al, 1999;Kil and Carlin, 2000;Tsacoumangos et al, 2005). Individual clones with matched levels of expression were selected by sterile cell sorting by flow cytometry after cells were stained with a human-specific EGFR antibody.…”

Section: Methodsmentioning

confidence: 99%

“…As EGFR recycling is known to be relatively slow compared to internalization (approximately 15 min versus 4-5 min, respectively) (Wiley, 2003), the net effect of the 679-AA mutation is to increase the pool of receptors in early endosomes compared to wild-type receptors. We have also demonstrated that 679-LL is an a-helical stabilizing motif, distinguishing it from other dileucine-based sorting signals with obligatory aminoterminal acidic residues that are recognized in the form of an extended b or b-like conformation and suggesting that it has a novel mode of action (Bonifacino and Traub, 2003;Tsacoumangos et al, 2005). Furthermore, EGFRs with a mutated 679-AA sequence interact with c-Cbl and undergo protein ubiquitination suggesting this protein modification is not sufficient for EGFR downregulation Tsacoumangos et al, 2005).…”

Section: Introductionmentioning

confidence: 91%

Gab1 signaling is regulated by EGF receptor sorting in early endosomes

et al. 2006

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Although combinatorial signaling through the ErbB network is implicated in certain types of human cancer, the specifics of how particular receptors contribute to the transformed phenotype are not well understood. The goal of this study was to identify epidermal growth factor (EGF) receptor-dependent cell signaling abnormalities specifically associated with mutations in a previously described 679-LL lysosomal sorting signal, which restrict ligand-dependent receptor downregulation by promoting recycling. Importantly, the 679-LL signal is not conserved in any of the other members of the ErbB receptor family suggesting its physiological function may be tightly regulated during EGF receptor-dependent signaling. Our data indicate that cells expressing receptors with an inactive 679-AA signal are rapidly transported to Rab4 þ early endosomes after they are internalized in contrast to wild-type receptors that are localized to early endocytic antigen 1 (EEA1) þ early endosomes. Divergent trafficking in early endosomes is associated with prolonged activation of p44/42 mitogen-activated protein kinases (MAPK) but not Akt. Gab1 appears to be the critical signaling molecule facilitating prolonged MAPK signaling, and activated Gab1 is recruited to early endosomes in 679-AA receptor-expressing cells. Activated Gab1 is also recruited to early endosomes in breast cancer cells characterized by high levels of EGF receptor-ErbB2 heterodimers, suggesting 679-AA expressing cells recapitulate certain aspects of EGF receptor signaling and transformation by activated ErbB2. Phosphatidylinositol 3-kinase (PI3K)-dependent membrane translocation known to be important for maintaining Gab1 activity in other settings was dispensable. We conclude that 679-LL has dual functions in EGF receptor trafficking and threshold signaling through a subset of signaling molecules including p44/42 MAPK and Gab1.

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A novel dileucine lysosomal-sorting-signal mediates intracellular EGF-receptor retention independently of protein ubiquitylation

Cited by 20 publications

References 83 publications

Functional roles of short sequence motifs in the endocytosis of membrane receptors

Functional roles of short sequence motifs in the endocytosis of membrane receptors

A Tyrosine-Based Signal Plays a Critical Role in the Targeting and Function of Adenovirus RIDα Protein

Gab1 signaling is regulated by EGF receptor sorting in early endosomes

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