Biochemical and Cellular Analysis Reveals Ligand Binding Specificities, a Molecular Basis for Ligand Recognition, and Membrane Association-dependent Activities of Cripto-1 and Cryptic

Aykul, Senem; Parenti, Anthony; Chu, Kit Yee; Reske, Jake J.; Floer, Monique; Ralston, Amy; Martı́nez-Hackert, Erik

doi:10.1074/jbc.m116.747501

Cited by 13 publications

(13 citation statements)

References 68 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The choice of type I receptor in the signaling complex is the main determinant of which of two signaling pathways is activated: Smad1/5/8, when the type I receptors are ACVRL1, ACVR1, BMPR1A, or BMPR1B; and Smad2/3, when the type I receptors are ACVR1B, TGFBR1, or ACVR1C. Activin A utilizes ACVR1B as its type I receptor in conjunction with the type II receptors ACVR2A, ACVR2B, and, to a lesser extent, BMPR2 to signal through Smad2/3 ( Aykul et al, 2017 ). The biological functions of Activin A have been investigated widely using multiple approaches ( Makanji et al, 2014 ; Namwanje and Brown, 2016 ) including reverse genetics experiments wherein the gene encoding for Activin A – Inhba – has been ‘knocked out’ ( Archambeault and Yao, 2010 ; Matzuk et al, 1995 ; Pangas et al, 2007 ).…”

Section: Introductionmentioning

confidence: 99%

Activin A forms a non-signaling complex with ACVR1 and type II Activin/BMP receptors via its finger 2 tip loop

Aykul

Corpina

Goebel

et al. 2020

eLife

Self Cite

View full text Add to dashboard Cite

Activin A functions in BMP signaling in two ways: it either engages ACVR1B to activate Smad2/3 signaling or binds ACVR1 to form a non-signaling complex (NSC). Although the former property has been studied extensively, the roles of the NSC remain unexplored. The genetic disorder fibrodysplasia ossificans progressiva (FOP) provides a unique window into ACVR1/Activin A signaling because in that disease Activin can either signal through FOP-mutant ACVR1 or form NSCs with wild-type ACVR1. To explore the role of the NSC, we generated ‘agonist-only’ Activin A muteins that activate ACVR1B but cannot form the NSC with ACVR1. Using one of these muteins, we demonstrate that failure to form the NSC in FOP results in more severe disease pathology. These results provide the first evidence for a biological role for the NSC in vivo and pave the way for further exploration of the NSC’s physiological role in corresponding knock-in mice.

show abstract

Section: Introductionmentioning

confidence: 99%

Activin A forms a non-signaling complex with ACVR1 and type II Activin/BMP receptors via its finger 2 tip loop

Aykul

Corpina

Goebel

et al. 2020

eLife

Self Cite

View full text Add to dashboard Cite

show abstract

“…We showed here that four cripto-1 antibodies bound, to a varying degree, to geltrex matrix which contains several proteins containing EGF-domains. [51][52][53][54][55] Furthermore, cripto-1 function has been shown to differ according to whether its membrane-anchored or soluble. Since cripto-1 is a surface-anchored protein and that few of the reported cripto-1 interaction partners such as TGF-β and Wnt proteins are secreted, it cannot be ruled out that cripto-1 is present in ECM such as geltrex.…”

Section: Discussionmentioning

confidence: 99%

“…This result either means that cripto-1 is present in geltrex matrix or that the antibodies cross-react and would need specific binding studies to elucidate. 53 Cripto-1 has been shown to antagonize activin and TGF-β mediated activation of ALK/activin receptors, in opposition to its possible importance in nodal-mediated activation of these receptors. 5,37-39 However, the binding differences were seen between the cripto-1 antibodies still poses a concern.…”

Section: Discussionmentioning

confidence: 99%

An evaluation of different Cripto‐1 antibodies and their variable results

Gudbergsson

Duroux

2019

J of Cellular Biochemistry

View full text Add to dashboard Cite

Cripto‐1 is a protein expressed during embryonal development and has been linked to several malignant processes in cancer. Since the discovery of cripto‐1 in the late 1980s, it has become a subject of biomarker investigation in several types of cancer which in many cases relies on immunolocalization of cripto‐1 using antibodies. Investigating cripto‐1 expression and localization in primary glioblastoma cells, we discovered nonspecific binding of cripto‐1 antibody to the extracellular matrix Geltrex. A panel of four cripto‐1 antibodies was investigated with respect to their binding to the Geltrex matrix and to the cripto‐1 positive control cells NTERA2. The cripto‐1 expression was varied for the different antibodies with respect to cellular localization and fixation methods. To further elaborate on these findings, we present a systematic review of cripto‐1 antibodies found in the literature and highlight some possible cross reactants with data on sequence alignments and structural comparison of EGF domains.

show abstract

“…The choice of type I receptor in the signaling complex is the main determinant of which of two signaling pathways is activated: Smad1/5/8, when the type I receptors are ACVRL1, ACVR1, BMPR1A, or BMPR1B; and Smad2/3, when the type I receptors are ACVR1B, TGFBR1, or ACVR1C. Activin A utilizes ACVR1B as its type I receptor in conjunction with the type II receptors ACVR2A, ACVR2B, and, to a lesser extent, BMPR2 to signal through Smad2/3 (Aykul et al, 2017). The biological functions of Activin A have been investigated widely using multiple approaches (Makanji et al, 2014;Namwanje & Brown, 2016) including reverse genetics experiments wherein the gene encoding for Activin A -Inhba -has been 'knocked out' (Archambeault & Yao, 2010;Matzuk et al, 1995;Pangas et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

The finger 2 tip loop of Activin A is required for the formation of its non-signaling complex with ACVR1 and type II Bone Morphogenetic Protein receptors

Aykul

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

Activin A functions in BMP signaling in two ways: it either engages ACVR1B to activate Smad2/3 signaling or binds ACVR1 to form a non-signaling complex (NSC). Although the former property has been studied extensively, the roles of the NSC remain unexplored. The genetic disorder fibrodysplasia ossificans progressiva (FOP) provides a unique window into ACVR1/Activin A signaling because in that disease Activin can either signal through FOPmutant ACVR1 or form NSCs with wild type ACVR1. To explore the role of the NSC, we generated 'agonist-only' Activin A muteins that activate ACVR1B but cannot form the NSC with ACVR1. Using one of these muteins we demonstrate that failure to form the NSC in FOP results in more severe disease pathology. These results provide the first evidence for a biological role for the NSC in vivo and pave the way for further exploration of the NSC's physiological role in corresponding knock-in mice. Impact StatementThe signaling complex formed by Activin A and ACVR1 is operant in vivo and is required to temper the degree of heterotopic ossification in the genetic disorder fibrodysplasia ossificans progressiva.

show abstract

Biochemical and Cellular Analysis Reveals Ligand Binding Specificities, a Molecular Basis for Ligand Recognition, and Membrane Association-dependent Activities of Cripto-1 and Cryptic

Abstract: Edited by Norma Allewell

Cited by 13 publications

References 68 publications

Activin A forms a non-signaling complex with ACVR1 and type II Activin/BMP receptors via its finger 2 tip loop

Activin A forms a non-signaling complex with ACVR1 and type II Activin/BMP receptors via its finger 2 tip loop

An evaluation of different Cripto‐1 antibodies and their variable results

The finger 2 tip loop of Activin A is required for the formation of its non-signaling complex with ACVR1 and type II Bone Morphogenetic Protein receptors

Contact Info

Product

Resources

About