Membrane-anchored growth factor, HB-EGF, on the cell surface targeted to the inner nuclear membrane

Hieda, Miki; Isokane, Mayumi; Koizumi, Michiko; Higashi, Chiduru; Tachibana, Taro; Shudou, Masachika; Taguchi, Tomohiko; Hieda, Yohki; Higashiyama, Shigeki

doi:10.1083/jcb.200710022

Cited by 69 publications

(83 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…However, unlike the EGFR family, which contains NLSs (36), these ligands do not contain NLSs. Interestingly, pro-HB-EGF has been shown to be targeted to the INM, yet no interaction of pro-HB-EGF with importin proteins has been detected, probably because of a lack of NLSs (42). Whether these ligands translocate via active transport, as larger molecules do, or via passive diffusion, as smaller molecules do, is unclear.…”

Section: Discussionmentioning

confidence: 99%

Membrane-bound Trafficking Regulates Nuclear Transport of Integral Epidermal Growth Factor Receptor (EGFR) and ErbB-2

Wang

Lee

et al. 2012

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background: EGFR is translocated to the inner nuclear membrane through the INTERNET (integral trafficking from the ER to the nuclear envelope transport) pathway. Results: INTERNET regulates EGFR and ErbB-2 but not FGFR-1. Conclusion: At least two different pathways of nuclear transport exist for cell surface receptors.Significance: This provides a new direction for investigating the trafficking mechanisms of various nuclear RTKs.

show abstract

Section: Discussionmentioning

confidence: 99%

Membrane-bound Trafficking Regulates Nuclear Transport of Integral Epidermal Growth Factor Receptor (EGFR) and ErbB-2

Wang

Lee

et al. 2012

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…To determine if Zmpste24-HA 469 localizes to the INM in addition to the ER membrane, we used standard indirect IF and compared the HA immunostaining pattern in digitonin and TX-100 -permeabilized cells. Digitonin permeabilizes the plasma membrane, but not the nuclear envelope (Adam et al, 1990;Hieda et al, 2008). This is in contrast to TX-100, which permeabilizes all cellular membranes.…”

mentioning

confidence: 88%

Analysis of Prelamin A Biogenesis Reveals the Nucleus to be a CaaX Processing Compartment

Barrowman¹,

Hamblet²,

George³

et al. 2008

MBoC

View full text Add to dashboard Cite

Proteins establish and maintain a distinct intracellular localization by means of targeting, retention, and retrieval signals, ensuring most proteins reside predominantly in one cellular location. The enzymes involved in the maturation of lamin A present a challenge to this paradigm. Lamin A is first synthesized as a 74-kDa precursor, prelamin A, with a C-terminal CaaX motif and undergoes a series of posttranslational modifications including CaaX processing (farnesylation, aaX cleavage and carboxylmethylation), followed by endoproteolytic cleavage by Zmpste24. Failure to cleave prelamin A results in progeria and related premature aging disorders. Evidence suggests prelamin A is imported directly into the nucleus where it is processed. Paradoxically, the processing enzymes have been shown to reside in the cytosol (farnesyltransferase), or are ER membrane proteins (Zmpste24, Rce1, and Icmt) with their active sites facing the cytosol. Here we have reexamined the cellular site of prelamin A processing, and show that the mammalian and yeast processing enzymes Zmpste24 and Icmt exhibit a dual localization to the inner nuclear membrane, as well as the ER membrane. Our findings reveal the nucleus to be a physiologically relevant location for CaaX processing, and provide insight into the biology of a protein at the center of devastating progeroid diseases. INTRODUCTIONThe nuclear envelope consists of an inner and outer membrane. The outer nuclear membrane (ONM) is continuous with the endoplasmic reticulum (ER) and connects with the inner nuclear membrane (INM) at the nuclear pore membrane (POM; Lusk et al., 2007). Integral membrane proteins that reside in the INM are initially inserted into the endoplasmic reticulum (ER) membrane and move via the POM to the INM where they maintain a concentrated localization by binding to chromatin or tethering to the nuclear lamina (Powell and Burke, 1990;Soullam and Worman, 1993;Holmer and Worman, 2001;Ohba et al., 2004;Lusk et al., 2007;Schirmer and Foisner, 2007). Until recently, conventional wisdom held that the localization of proteins to either the ER membrane or the INM is mutually exclusive. For example, proteins that are found within the INM, such as LAP1, are not generally found throughout the ER/ONM; likewise, ER proteins such as HMG-CoA reductase are strictly localized to the ER (Wright et al., 1988;Powell and Burke, 1990;Deng and Hochstrasser, 2006). It was recently shown that a notable exception to this paradigm is the yeast E3 ubiquitin ligase, Doa10p. Doa10p was long known to reside in the ER membrane (Swanson et al., 2001;Kreft et al., 2006). However, recent data indicate that Doa10p exhibits dual steady-state localizations, residing and functioning in both the ER membrane where it mediates ER-associated degradation of membrane and secretory proteins, and in the INM where it mediates degradation of the nuclear transcription factor MAT␣2 (Deng and Hochstrasser, 2006).The present study documents another exception to the mutual exclusivity of ER membrane and INM localizati...

show abstract

“…The second pathway is receptor independent, termed reverse signaling, and involves nuclear localization and signaling by the ICD of the ligand precursor . Although the mechanisms for production and nuclear trafficking of each ICD seem to be distinct, a common feature of reverse signaling is the transcriptional regulation of gene expression (Bao et al, 2004;Bao et al, 2003;Hieda et al, 2008;Higashiyama et al, 2008;Isokane et al, 2008;Nanba et al, 2003). In the present study, we show that the BTC precursor (proBTC) can undergo sequential processing by ADAM10 and presenilin1/2-dependent -secretase to generate BTC-ICD.…”

Section: Discussionmentioning

confidence: 57%

“…Several ErbB-ligand precursors can translocate to the nucleus by distinct mechanisms and influence gene expression (Bao et al, 2003;Hieda et al, 2008;Higashiyama et al, 2008;Isokane et al, 2008). To determine whether the BTC-ICD translocates to the nucleus, constructs encoding the ICD of BTC with N-or Cterminal EGFP tags were generated (BTC-ICD-Only).…”

Section: Non-palmitoylated Btc-icd Translocates To the Nucleusmentioning

confidence: 99%

Sequential and γ-secretase-dependent processing of the betacellulin precursor generates a palmitoylated intracellular-domain fragment that inhibits cell growth

Stoeck

Dempsey

2010

Journal of Cell Science

View full text Add to dashboard Cite

SummaryBetacellulin (BTC) belongs to the family of epidermal growth factor (EGF)-like growth factors that are expressed as transmembrane precursors and undergo proteolytic ectodomain shedding to release soluble mature ligands. BTC is a dual-specificity ligand for ErbB1 and ErbB4 receptors, and can activate unique signal-transduction pathways that are beneficial for the function, survival and regeneration of pancreatic b-cells. We have previously shown that BTC precursor (proBTC) is cleaved by ADAM10 to generate soluble ligand and a stable, transmembrane remnant (BTC-CTF). In this study, we analyzed the fate of the BTC-CTF in greater detail. We demonstrated that proBTC is cleaved by ADAM10 to produce BTC-CTF, which then undergoes intramembrane processing by presenilin-1-and/or presenilin-2-dependent -secretase to generate an intracellular-domain fragment (BTC-ICD). We found that the proBTC cytoplasmic domain is palmitoylated and that palmitoylation is not required for ADAM10-dependent cleavage but is necessary for the stability and -secretase-dependent processing of BTC-CTF to generate BTC-ICD. Additionally, palmitoylation is required for nuclear-membrane localization of BTC-ICD, as demonstrated by the redistribution of non-palmitoylated BTC-ICD mutant to the nucleoplasm. Importantly, a novel receptor-independent role for BTC-ICD signaling is suggested by the ability of BTC-ICD to inhibit cell growth in vitro.

show abstract

Membrane-anchored growth factor, HB-EGF, on the cell surface targeted to the inner nuclear membrane

Cited by 69 publications

References 30 publications

Membrane-bound Trafficking Regulates Nuclear Transport of Integral Epidermal Growth Factor Receptor (EGFR) and ErbB-2

Membrane-bound Trafficking Regulates Nuclear Transport of Integral Epidermal Growth Factor Receptor (EGFR) and ErbB-2

Analysis of Prelamin A Biogenesis Reveals the Nucleus to be a CaaX Processing Compartment

Sequential and γ-secretase-dependent processing of the betacellulin precursor generates a palmitoylated intracellular-domain fragment that inhibits cell growth

Contact Info

Product

Resources

About