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ErbB2 overexpression is seen in a variety of cancers and is strongly associated with metastatic events and
inhibited degradation of activated receptors. Lacking intrinsic ability to self-phosphorylate, ErbB2 receptors
bind with other members of the ErbB family to induce activation and potentiate signal transduction,
frequently resulting in increased COX-2 and AKT activity due to nuclear localization, events commonly seen
in metastasis.

ErbB3 receptor
ErbB3 is a catalytically inhibited member of the ErbB family, bearing a mutated tyrosine kinase domain
and relying on heterodimerization partners for phosphorylation. As such, ErbB3 frequently presents with
decreased levels of ubiquitination in comparison to EGFR, emphasizing the inefficiency of ErbB3 to be
targeted to the lysosome [107] . Heterodimers between ErbB2 and ErbB3 lead to strong activation of the MAPK
and PI3K/AKT pathways, promoting survival and proliferation by ErbB2 and ErbB3, respectively [108-110] .
Through these signaling pathways ErbB3 activity is associated with loss of cellular differentiation and
increased expression of MUC1 in carcinomas, as well as driving proliferation in ErbB2-positive breast cancer
cells lines [108,111] . ErbB3 is subject to significantly slower rates of endocytosis than EGF-bound EGFR due to
the anti-internalization regions within the C-terminus, allowing for longer periods of receptor activation
(when in a heterodimer) [71,112] . This delayed trafficking results in perinuclear accumulation, thereby allowing
nuclear localization via retrotranslocation [113] . Once in the nucleus, ErbB3 presents in an activated, uncleaved
format, capable of associating with the Cyclin D1 promoter to drive cell proliferation, similar to the
mechanism seen in EGFR [54,56,114] . Clinical data has shown in prostate cancer, nuclear localization of ErbB3
present in 100 percent of hormone-refractory samples and 40 percent of hormone-sensitive samples, in
contrast to the negligible amount seen in normal prostate tissue, directly associated with disease progression
risks [115] . Nuclear ErbB3 also presents at higher frequency in prostate cancer metastases (particularly bone)
than in primary tumor sites [116] , indicating that retrotranslocated ErbB3 is likely involved in the metastasis of
prostate cancers.

ErbB4 receptor
The fourth and final member of the ErbB family, ErbB4 maintains homology to ErbB1- capable of binding
ligands (EPR, HB-EGF, BTC, and neuregulins 1-4) and a tyrosine kinase domain capable of catalytic
activation [112,117] . Once bound to a ligand, ErbB4 promotes signal transduction through a host of pathways,
[118]
including PLCɣ, PI3K, and STAT .

Post-activation, ErbB4 is subject to dual-protease cleavage in both the extracellular domain and the
transmembrane domain, resulting in an active, cleaved cytoplasmic domain capable of nuclear translocation
(upon binding to neuregulin). ErbB4 activity is highly associated with poor prognosis and increased
metastasis in Ewing sarcoma, activating PI3K-AKT and altering FAKs to drive invasion [119] . Expression of
ErbB4 also increases in colorectal cancer as disease stage progresses, indicating a potential role in driving
cancer progression, though its expression is associated with improved prognosis in estrogen-receptor positive
breast cancers [120,121] . Highly enriched in neuronal plaques of patients with Alzheimer disease, nuclear
localization can lead to transcriptional activation of genes that regulate neurodegeneration [118] . To achieve
nuclear localization, it is possible that active, cleaved ErbB4 reaches the Sec61 translocon in the ER and is
processed while avoiding ERAD-ubiquitin-associated proteolysis, in a mechanism similar to EGFR nuclear
translocation [86,118] .

In addition to the tyrosine kinase receptors described above, at least two non-tyrosine kinase receptors, ILR2
and TGF-β receptor, also undergo retrotranslocation in cancer.

ILR2
Found in fibroblasts, epithelial, and neuronal cells, ILR2, upon ligand binding is internalized and targeted
for degradation through acidification, similar to EGFR and the transferrin receptor [59,122,123] . ILR2 has also