The Role of BCA2 in the Endocytic Trafficking of EGFR and Significance as a Prognostic Biomarker in Cancer

Wymant, Jennifer; Hiscox, Stephen Edward; Westwell, Andrew D.; Urbé, Sylvie; Clague, Michael J.; Jones, Arwyn Tomos

doi:10.7150/jca.15055

Cited by 12 publications

(14 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As shown in Fig 5A, TfR1 colocalized with AP-1 in the PNR and the cytoplasm. This is consistent with the previously reported PNR of TfR1 [17][18][19][20][40][41][42]. Interestingly, TfR1 also colocalized with LZTFL1 in the PNR and the cytoplasm in a pattern similar to that of AP-1 (Fig 5B).…”

Section: Lztfl1 Interacts With Tfr1-bound Ap-1supporting

confidence: 92%

Leucine zipper transcription factor-like 1 binds adaptor protein complex-1 and 2 and participates in trafficking of transferrin receptor 1

Promchan

Natarajan

2020

PLoS ONE

View full text Add to dashboard Cite

LZTFL1 participates in immune synapse formation, ciliogenesis, and the localization of ciliary proteins, and knockout of LZTFL1 induces abnormal distribution of heterotetrameric adaptor protein complex-1 (AP-1) in the Lztfl1-knockout mouse photoreceptor cells, suggesting that LZTFL1 is involved in intracellular transport. Here, we demonstrate that in vitro LZTFL1 directly binds to AP-1 and AP-2 and coimmunoprecipitates AP-1 and AP-2 from cell lysates. DxxFxxLxxxR motif of LZTFL1 is essential for these bindings, suggesting LZTFL1 has roles in AP-1 and AP-2-mediated protein trafficking. Since AP-1 and AP-2 are known to be involved in transferrin receptor 1 (TfR1) trafficking, the effect of LZTFL1 on TfR1 recycling was analyzed. TfR1, AP-1 and LZTFL1 from cell lysates could be coimmunoprecipitated. However, pull-down results indicate there is no direct interaction between TfR1 and LZTFL1, suggesting that LZTFL1 interaction with TfR1 is indirect through AP-1. We report the colocalization of LZTFL1 and AP-1, AP-1 and TfR1 as well as LZTFL1 and TfR1 in the perinuclear region (PNR) and the cytoplasm, suggesting a potential complex between LZTFL1, AP-1 and TfR1. The results from the disruption of adaptin recruitment with brefeldin A treatment suggested ADP-ribosylation factor-dependent localization of LZFL1 and AP-1 in the PNR. Knockdown of AP-1 reduces the level of LZTFL1 in the PNR, suggesting that AP-1 plays a role in LZTFL1 trafficking. Knockout of LZTFL1 reduces the cell surface level and the rate of internalization of TfR1, leading to a decrease of transferrin uptake, efflux, and internalization. However, knockout of LZTFL1 did not affect the cell surface levels of epidermal growth factor receptor and cation-independent mannose 6-phosphate receptor, indicating that LZTFL1 specifically regulates the cell surface level of TfR1. These data support a novel role of LZTFL1 in regulating the cell surface TfR1 level by interacting with AP-1 and AP-2.

show abstract

Section: Lztfl1 Interacts With Tfr1-bound Ap-1supporting

confidence: 92%

Leucine zipper transcription factor-like 1 binds adaptor protein complex-1 and 2 and participates in trafficking of transferrin receptor 1

Promchan

Natarajan

2020

PLoS ONE

View full text Add to dashboard Cite

show abstract

“…It was 7 hr before HER2 was significantly depleted by Tz ± crosslinking. This represents a relatively low rate of endocytic downregulation compared with a prototypical receptor such as ligandbound EGFR where the majority of the receptor degrades within 1 hr of epidermal growth factor (EGF) stimulation (38). There are conflicting reports in the literature about the ability of Tz to drive lysosomal degradation of HER2 (6) but our data adds to the body of evidence that the antibody can induce receptor downregulation.…”

Section: Discussionmentioning

confidence: 82%

Strategic Trastuzumab Mediated Crosslinking Driving Concomitant HER2 and HER3 Endocytosis and Degradation in Breast Cancer

Wymant¹,

Sayers²,

Muir³

et al. 2020

J. Cancer

View full text Add to dashboard Cite

Efficacious anticancer therapies for targeting plasma membrane receptors with antibody based therapeutics are often contingent on sufficient endocytic delivery of receptor and conjugate to lysosomes. This results in downregulation of receptor activity and, in the case of antibody-drug conjugates (ADCs), intracellular release of a drug payload. The oncogenic receptor HER2 is a priority therapeutic target in breast cancer. Known as an "endocytosis resistant" receptor, HER2 thwarts the receptor downregulating efficiency of the frontline treatment trastuzumab and reduces the potential of trastuzumab-based therapies such as trastuzumab-emtansine. We previously demonstrated that strategically inducing trastuzumab and HER2 crosslinking in breast cancer cells promoted endocytosis and lysosomal delivery of the HER2-trastuzumab complex, stimulating downregulation of the receptor. Here we reveal that HER3, but not EGFR, is also concomitantly downregulated with HER2 after crosslinking. This is accompanied by strong activation of MEK/ERK pathway that we show does not directly contribute to HER2/trastuzumab endocytosis. We show that crosslinking induced trastuzumab endocytosis occurs via clathrin-dependent and independent pathways and is an actin-dependent process. Detailed ultrastructural studies of the plasma membrane highlight crosslinking-specific remodelling of microvilli and induction of extensive ruffling. Investigations in a cell model of acquired trastuzumab resistance demonstrate, for the first time, that they are refractory to crosslinking induced HER2 endocytosis and downregulation. This implicates further arrest of HER2 internalisation in developing trastuzumab resistance. Overall our findings highlight the potential of receptor crosslinking as a therapeutic strategy for cancer while exposing the ability of cancer cells to develop resistance via endocytic mechanisms.

show abstract

“…Accordingly, the gene was renamed Breast Cancer Associated gene 2 (BCA2) [67,68]. Overexpression of BCA2 in HeLa cells causes failure of RAB7 membrane association and thus RAB7 remains in the cytosol, not being able to carry out its functions on the endosomal membranes [69]. As a consequence, EGFR degradation is inhibited [69].…”

Section: Rab7a In Cancer Progressionmentioning

confidence: 99%

Role of the RAB7 Protein in Tumor Progression and Cisplatin Chemoresistance

Guerra

Bucci

2019

Cancers

View full text Add to dashboard Cite

RAB7 is a small guanosine triphosphatase (GTPase) extensively studied as regulator of vesicular trafficking. Indeed, its role is fundamental in several steps of the late endocytic pathway, including endosome maturation, transport from early endosomes to late endosomes and lysosomes, clustering and fusion of late endosomes and lysosomes in the perinuclear region and lysosomal biogenesis. Besides endocytosis, RAB7 is important for a number of other cellular processes among which, autophagy, apoptosis, signaling, and cell migration. Given the importance of RAB7 in these cellular processes, the interest to study the role of RAB7 in cancer progression is widely grown. Here, we describe the current understanding of oncogenic and oncosuppressor functions of RAB7 analyzing cellular context and other environmental factors in which it elicits pro and/or antitumorigenic effects. We also discuss the role of RAB7 in cisplatin resistance associated with its ability to regulate the late endosomal pathway, lysosomal biogenesis and extracellular vesicle secretion. Finally, we examined the potential cancer therapeutic strategies targeting the different molecular events in which RAB7 is involved.

show abstract

The Role of BCA2 in the Endocytic Trafficking of EGFR and Significance as a Prognostic Biomarker in Cancer

Cited by 12 publications

References 48 publications

Leucine zipper transcription factor-like 1 binds adaptor protein complex-1 and 2 and participates in trafficking of transferrin receptor 1

Leucine zipper transcription factor-like 1 binds adaptor protein complex-1 and 2 and participates in trafficking of transferrin receptor 1

Strategic Trastuzumab Mediated Crosslinking Driving Concomitant HER2 and HER3 Endocytosis and Degradation in Breast Cancer

Role of the RAB7 Protein in Tumor Progression and Cisplatin Chemoresistance

Contact Info

Product

Resources

About