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Again Wnt binds and activates to Frizzled.
In this case however activated Frizzled causes a coupled G-protein to activate a phospholipase (PLC), which interacts with and splits PIP into DAG and IP.
IP can then bind to a receptor on the endoplasmic reticulum to release intracellular calcium stores, to induce calcium-dependent gene expression.
The Wnt signaling pathways are critical in cell-cell signaling during normal development and embryogenesis and required for maintenance of adult tissue, therefore it is not difficult to understand why disruption in Wnt signaling pathways can promote human degenerative disease and cancer.
The Wnt signaling pathways are complex, involving many different elements, and therefore have many targets for misregulation.
Mutations that cause constitutive activation of the Wnt signaling pathway lead to tumor formation and cancer.
Aberrant activation of the Wnt pathway can lead to increase cell proliferation.
Current research is focused on the action of the Wnt signaling pathway the regulation of stem cell choice to proliferate and self renew.
This action of Wnt signaling in the possible control and maintenance of stem cells, may provide a possible treatment in cancers exhibiting aberrant Wnt signaling.
"TGF" (Transforming Growth Factor) is a family of proteins that includes 33 members that encode dimeric, secreted polypeptides that regulate development.
Many developmental processes are under its control including gastrulation, axis symmetry of the body, organ morphogenesis, and tissue homeostasis in adults.
All TGF-β ligands bind to either Type I or Type II receptors, to create heterotetramic complexes.
The TGF-β pathway regulates many cellular processes in developing embryo and adult organisms, including cell growth, differentiation, apoptosis, and homeostasis.
There are five kinds of type II receptors and seven types of type I receptors in humans and other mammals.
These receptors are known as "dual-specificity kinases" because their cytoplasmic kinase domain has weak tyrosine kinase activity but strong serine/threonine kinase activity.
When a TGF-β superfamily ligand binds to the type II receptor, it recruits a type I receptor and activates it by phosphorylating the serine or threonine residues of its "GS" box.
This forms an activation complex that can then phosphorylate SMAD proteins through phosphorylation.
There are three classes of SMADs:
Examples of SMADs in each class:
The TGF-β superfamily activates members of the SMAD family, which function as transcription factors.
Specifically, the type I receptor, activated by the type II receptor, phosphorylates R-SMADs that then bind to the co-SMAD, SMAD4.
The R-SMAD/Co-SMAD forms a complex with importin and enters the nucleus, where they act as transcription factors and either up-regulate or down-regulate in the expression of a target gene.
Specific TGF-β ligands will result in the activation of either the SMAD2/3 or the SMAD1/5 R-SMADs.
For instance, when activin, Nodal, or TGF-β ligand binds to the receptors, the phosphorylated receptor complex can activate SMAD2 and SMAD3 through phosphorylation.
However, when a BMP ligand binds to the receptors, the phosphorylated receptor complex activates SMAD1 and SMAD5.
Then, the Smad2/3 or the Smad1/5 complexes form a dimer complex with SMAD4 and become transcription factors.
Though there are many R-SMADs involved in the pathway, there is only one co-SMAD, SMAD4.
Non-Smad signaling proteins contribute to the responses of the TGF-β pathway in three ways.
First, non-Smad signaling pathways phosphorylate the Smads.
Second, Smads directly signal to other pathways by communicating directly with other signaling proteins, such as kinases.
Finally, the TGF-β receptors directly phosphorylate non-Smad proteins.
This family includes TGF-β1, TGF-β2, TGF-β3, and TGF-β5.
They are involved in positively and negatively regulation of cell division, the formation of the extracellular matrix between cells, apoptosis, and embryogenesis.
They bind to TGF-β type II receptor (TGFBRII).
TGF-β1 stimulates the synthesis of collagen and fibronectin and inhibits the degradation of the extracellular matrix degradation.
Ultimately, it increases the production of extracellular matrix by epithelial cells.
TGF-β proteins regulate epithelia by controlling where and when they branch to form kidney, lung, and salivary gland ducts.
Members of the BMP family were originally found to induce bone formation, as their name suggests.
However, BMPs are very multifunctional and can also regulate apoptosis, cell migration, cell division, and differentiation.
They also specify the anterior/posterior axis, induce growth, and regulate homeostasis.
The BMPs bind to the bone morphogenetic protein receptor type II (BMPR2).
Some of the proteins of the BMP family are BMP4 and BMP7.
BMP4 promotes bone formation, causes cell death, or signals the formation of epidermis, depending on the tissue it is acting on.
BMP7 is crucial for kidney development, sperm synthesis, and neural tube polarization.
Both BMP4 and BMP7 regulate mature ligand stability and processing, including degrading ligands in lysosomes.
BMPs act by diffusing from the cells that create them.
Growth factor and clotting factors are paracrine signaling agents.
The local action of growth factor signaling plays an especially important role in the development of tissues.
Also, retinoic acid, the active form of vitamin A, functions in a paracrine fashion to regulate gene expression during embryonic development in higher animals.
In insects, Allatostatin controls growth though paracrine action on the corpora allata.
In mature organisms, paracrine signaling is involved in responses to allergens, tissue repair, the formation of scar tissue, and blood clotting.
Daniel Okrent
Daniel Okrent (born April 2, 1948) is an American writer and editor.
He is best known for having served as the first public editor of "The New York Times" newspaper, inventing Rotisserie League Baseball, and for writing several books (such as "Last Call: The Rise and Fall of Prohibition", which served as a major source for the 2011 Ken Burns/Lynn Novick miniseries "Prohibition)".
In November 2011, "Last Call" won the Albert J. Beveridge prize, awarded by the American Historical Association to the year's best book of American history.His most recent book, published May 2019, is "The Guarded Gate: Bigotry, Eugenics, and the Law That Kept Two Generations of Jews, Italians, and Other European Immigrants Out of America".
Born to a Jewish family in Detroit, Michigan, Okrent graduated from Cass Technical High School in Detroit in 1965 and from the University of Michigan, where he worked on the university's student newspaper "The Michigan Daily".
Most of his career has been spent as an editor, at such places as Alfred A. Knopf; Harcourt, Brace, Jovanovich; "Esquire Magazine"; "New England Monthly"; "Life Magazine"; and Time, Inc.
His book "Great Fortune: The Epic of Rockefeller Center" (Viking, 2003) was a finalist for the Pulitzer Prize for History.
In October 2003, Okrent was named public editor for "The New York Times" following the Jayson Blair scandal.
He held this position until May 2005.
Okrent and Peter Gethers, having acquired the theatrical rights to the site and name of the web series "Old Jews Telling Jokes", co-wrote and co-produced a revue of that name.
It opened at the Westside Theatre in Manhattan on May 20, 2012.
On May 3, 2014, the University of Michigan awarded Okrent an honorary degree, Doctor of Humane Letters.
Since 2017, Okrent has been listed on the Advisory Board of the Secular Coalition for America.
He formulated what has become known as "Okrent's law" in an interview comment he made about his new job.
It states: "The pursuit of balance can create imbalance because sometimes something is true", referring to the phenomenon of the press providing legitimacy to fringe or minority viewpoints in an effort to appear even-handed.
Okrent invented Rotisserie League Baseball, the best-known form of fantasy baseball, in 1979.
The name comes from the fact that he proposed the idea to his friends while dining at La Rôtisserie Française restaurant in New York City.
Okrent's team in the Rotisserie League was called the "Okrent Fenokees", a pun on the Okefenokee Swamp.
He was one of the first two people inducted into the Fantasy Sports Hall of Fame.
Okrent was still playing Rotisserie as of 2009 under the team name Dan Druffs.
Despite having been credited with inventing fantasy baseball he has never been able to win a Rotisserie League.
His exploits of inventing Rotisserie League Baseball were chronicled in "Silly Little Game", part of the ESPN "30 for 30" documentary series, in 2010.
Okrent is also credited with inventing the baseball stat, WHIP.
At the time he referred to it as IPRAT, signifying "Innings Pitched Ratio".
In May 1981, Okrent wrote and "Sports Illustrated" published "He Does It by the Numbers".
This profile of the then-unknown Bill James launched James's career as baseball's foremost analyst.
In 1994, Okrent was filmed for his in-depth knowledge of baseball history for the Ken Burns documentary "Baseball".
During the nine-part series, a red-sweater-wearing Okrent delivered a detailed analysis of the cultural aspects of the national pastime, including a comparison of the dramatic Game 6 of the 1975 World Series between the Boston Red Sox and Cincinnati Reds to the conflict and character development in Russian novels.
In the late 1990s, as editor of new media at Time Inc., Okrent wrote about the future of magazine publishing.
He believed that the advancement of digital technologies would make it easier for people to read newspapers, magazines and books online.
In late 1999, Okrent made a prediction about the future of print media in the Hearst New Media Lecture at the Graduate School of Journalism of Columbia University.
He told his audience:
Okrent has participated in LearnedLeague under the name "OkrentD".
Julius Blank
Julius Blank (June 2, 1925 – September 17, 2011) was a semiconductor pioneer.
A member of the so-called traitorous eight, he left Nobel-winning physicist William Shockley's company to form Fairchild Semiconductor.
Blank was born and raised in Manhattan's Lower East Side, the youngest of three children of Jewish immigrants Charles and Gussie Blank.
His father made musical-instrument cases and luggage, and also worked as a Russian translator.
Julius Blank attended Erasmus Hall High School, graduating at 15.
He began taking classes at City College of New York while working at various jobs.
His first job, in a factory, motivated him to learn more, and he attended a trade school as well.
When he turned 18, he was drafted to serve in the U.S. Army in World War II.
He reported for active duty on July 5, 1943.
After basic infantry training, he was placed in the Army Specialized Training Program.
In April 1944, he was sent overseas, where he was injured in December 1944 during the Battle of Hürtgen Forest.
He was subsequently transferred to the Air Corps to serve as a machinist for airplane parts to overhaul radial engines.
He held a variety of positions during the war, gaining considerable experience in the practicalities of general engineering.
In 1946 he returned home, where he completed his Bachelor's degree in mechanical engineering from the City College of New York, financed by the G.I.
Bill.