cDNA cloning and molecular characterization of MSE55, a novel human serum constituent protein that displays bone marrow stromal/endothelial cell-specific expression.

Bahou, Wadie F.; Campbell, Alan D.; Wicha, Max S.

doi:10.1016/s0021-9258(19)49667-1

Cited by 25 publications

(6 citation statements)

References 41 publications

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“…The interaction of the G protein (in its GTPbound conformation) with an effector protein triggers a downstream signaling cascade. Many Cdc42 interacting proteins have been identified and proposed to be effector proteins (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16). These include: the p21-activated kinases (PAKs, 6, 7), the activated Cdc42-associated kinases (ACKs,8,9), and the Wiskott-Aldrich Syndrome proteins (WASPs,10,11).…”

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confidence: 99%

Residues in Cdc42 That Specify Binding to Individual CRIB Effector Proteins

et al. 2000

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Cdc42 is a member of the Rho family of small G proteins. Signal transduction events emanating from Cdc42 lead to cytoskeletal rearrangements, cell proliferation, and cell differentiation. Many effector proteins have been identified for Cdc42; however, it is not clear how certain effectors specifically recognize and bind to Cdc42, as opposed to Rac or Rho, or in many cases, which effector controls what cellular events. Mutations were introduced into Cdc42 at residues: Met1, Val8, Phe28, Tyr32, Val33, Thr35, Val36, Phe37, Asp38, Tyr40, Val42, Met45, Ile46, Glu127, Ala130, Asn132, Gln134, Lys135, and Leu174. Measurements were made of their equilibrium binding constants to the Cdc42 binding domains of the CRIB effectors ACK, PAK, and WASP and to the GTPase-activating protein Rho GAP. Generally, mutations in the effector loop have an equally deleterious effect on binding to all CRIB proteins tested, though the F37A mutation resulted in significant selectivity. Residues outside the effector loop were found to be important for binding of Cdc42 to CRIB containing proteins and also to contribute to selectivity. Mutations such as V42A and L174A resulted in large, selective changes in binding to specific CRIB effectors. Neither mutation resulted in alteration in PAK binding, whereas both severely disrupt binding to ACK and only L174A disrupted binding to WASP. These mutations are interpreted using the structures of the Cdc42/ACK and Cdc42/WASP complexes to give insight into how effectors can specifically recognize Cdc42. Those mutations in Cdc42 that inhibit certain interactions, while retaining others, should aid investigations of the role of specific effectors in Cdc42 signaling in vivo.

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confidence: 99%

Residues in Cdc42 That Specify Binding to Individual CRIB Effector Proteins

et al. 2000

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“…4B). Canonical markers of bone marrow sinusoidal endothelium were more highly expressed in endothelial cells from VEGFA + C cultures compared to VEGFA alone, including FLT4 (VEGFR4), CD34 , MCAM , ANGPT2 , COL4A1 , COL4A2 , ITGA2 , CDC42EP1 and the notch ligand DLL4 (24,37,43,44), while DLK1 – a negative regulator of hematopoiesis (45) – was significantly downregulated in VEGFA + C-stimulated organoids (Figs. 4B & 4C).…”

Section: Resultsmentioning

confidence: 99%

Human bone marrow organoids for disease modelling, discovery and validation of therapeutic targets in hematological malignancies

Khan

Colombo

Reyat

et al. 2022

Preprint

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A lack of models that recapitulate the complexity of human bone marrow has hampered mechanistic studies of normal and malignant hematopoiesis and the validation of novel therapies. Here, we describe a step-wise, directed-differentiation protocol in which organoids are generated from iPSCs committed to mesenchymal, endothelial and hematopoietic lineages. These 3-dimensional structures capture key features of human bone marrow - stroma, lumen-forming sinusoidal vessels and myeloid cells including pro-platelet forming megakaryocytes. The organoids supported the engraftment and survival of cells from patients with blood malignancies, including cancer types notoriously difficult to maintain ex vivo. Fibrosis of the organoid occurred following TGFβ ; stimulation and engraftment with myelofibrosis but not healthy donor-derived cells, validating this platform as a powerful tool for studies of malignant cells and their interactions within a human bone marrow-like milieu. This enabling technology is likely to accelerate discovery and prioritization of novel targets for bone marrow disorders and blood cancers.

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“…BORG3 is a minor exception, it lacks a BH2 domain (Hirsch et al, 2001; Joberty et al, 1999). All BORGs also have a basic region at their N‐terminus before the CRIB, and BORG5 has a heptad repeat of “PAANPPA” of unknown function (Bahou et al, 1992; Hirsch et al, 2001; Joberty et al, 1999). BORG2 also has a “putative actin binding domain” between the BH2 and BH3 domains (Figure 1).…”

Section: Borg Protein Organization and Structurementioning

confidence: 99%

“…The first BORG was discovered when a hemonectin antibody picked up an unidentified 55 kDa protein that contained a Cdc42/Rac Interactive Binding (CRIB) domain. This was initially named MSE55 and later renamed BORG5/Cdc42EP1 (Bahou et al, 1992). The other BORG family proteins were later discovered through a yeast two‐hybrid screen with a bait of TC10, a close relative of Cdc42.…”

Section: Introductionmentioning

confidence: 99%

BORG family proteins in physiology and human disease

Tomasso

Padrick

2023

Cytoskeleton

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The binder of rho GTPases (BORG)/Cdc42 effector proteins (Cdc42EP) family is composed of five Rho GTPase binding proteins whose functions and mechanism of actions are of emerging interest. Here, we review recent findings pertaining to the family as a whole and consider how these change our understanding of cellular organization. Recent studies have implicated BORGs in both fundamental physiology and in human diseases, mainly cancers. An emerging pattern suggests that BORG family members cancer‐promoting properties are related to their ability to regulate the cytoskeleton, with many impacting the organization of acto‐myosin stress fibers. This is consistent with the broader literature indicating that BORG family members are regulators of both the septin and actin cytoskeleton networks. The exact mechanism through which BORGs modify the cytoskeleton is not clear, but we consider here a few data‐supported and speculative possibilities. Finally, we delve into how the Rho GTPase Cdc42 modifies BORG function in cells. This remains open‐ended as Cdc42's effects on BORGs appear cell type‐ and cell state‐dependent. Collectively, these data point to the importance of the BORG family and suggest broader themes in their function and regulation.

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cDNA cloning and molecular characterization of MSE55, a novel human serum constituent protein that displays bone marrow stromal/endothelial cell-specific expression.

Cited by 25 publications

References 41 publications

Residues in Cdc42 That Specify Binding to Individual CRIB Effector Proteins

Residues in Cdc42 That Specify Binding to Individual CRIB Effector Proteins

Human bone marrow organoids for disease modelling, discovery and validation of therapeutic targets in hematological malignancies

BORG family proteins in physiology and human disease

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