Unique and Overlapping Functions of GSK-3 Isoforms in Cell Differentiation and Proliferation and Cardiovascular Development

Intensive study over the past 30 years has helped define the role of the GSK-3 (glycogen synthase kinase-3) family in a variety of physiological and pathophysiological processes. However, the majority of these studies have relied upon overexpression approaches or nonselective small molecule inhibitors. Herein, we examine recent data derived from studies in gene-targeted embryonic stem cells and knock-out mice in an attempt to define the role these protein kinases play in critical decisions made by stem/progenitor cells and by early lineage-committed cardiomyocytes during development. Intensive study over the past 30 years has helped define the role of the GSK-3 (glycogen synthase kinase-3) family in a variety of physiological and pathophysiological processes. However, the majority of these studies have relied upon overexpression approaches or nonselective small molecule inhibitors. Herein, we examine recent data derived from studies in gene-targeted embryonic stem cells and knock-out mice in an attempt to define the role these protein kinases play in critical decisions made by stem/progenitor cells and by early lineage-committed cardiomyocytes during development. The GSK-3 family of serine/threonine kinases was first identified as a negative regulator of glycogen synthase, the rate-limiting enzyme in glycogen synthesis (1Doble B.W. Woodgett J.R. J. Cell Sci. 2003; 116: 1175-1186Crossref PubMed Scopus (1744) Google Scholar, 2Frame S. Cohen P. Biochem. J. 2001; 359: 1-16Crossref PubMed Scopus (1266) Google Scholar). The family consists of two isoforms, α and β, which are 98% identical within their kinase domains but differ substantially in their N- and C-terminal sequences. Unlike most protein kinases, GSK-3 is typically active in unstimulated cells and is inhibited in response to a variety of inputs, including growth factors. Because GSK-3-mediated phosphorylation of substrates usually leads to inhibition of those substrates, the end result of growth factor-mediated inhibition of GSK-3 is typically functional activation of its downstream substrates.Traditionally, most attention has focused on the β-isoform of GSK-3. However, this bias appears to have arisen from two reports suggesting that mammalian was in to the in P. P. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar). However, in these the of of and was as we and to in of on studies in to play in embryonic protein kinase mice and in to glycogen in the B.W. S. Woodgett J.R. Cell PubMed Scopus Google Scholar). in J. Woodgett J.R. PubMed Scopus Google Scholar, J. S. Woodgett J. PubMed Scopus Google but of have in including glycogen synthase activation and glycogen S. B.W. Woodgett J.R. PubMed Scopus Google Scholar). of in the of the is to and the of in two of the in of the and of S. B.W. Woodgett J.R. PubMed Scopus Google Scholar). The of cells to and of these critical cells S. B.W. Woodgett J.R. PubMed Scopus Google Scholar). we on in this as we to and to of the isoforms, is to in that of the by in in or over the past years have GSK-3 as a critical regulator of in P. S. PubMed Scopus Google Scholar, P. J. PubMed Scopus Google Scholar, P. PubMed Scopus Google Scholar, J. PubMed Scopus Google Scholar, J. J. Woodgett J. Cohen P. PubMed Scopus Google Scholar). However, these studies typically have the small molecule which is GSK-3 and studies have cells or and from these studies a role the GSK-3 in including a role in the J. S. Woodgett J. PubMed Scopus Google Scholar, J. J. Woodgett J. Cohen P. PubMed Scopus Google Scholar, B.W. S. Woodgett J.R. PubMed Scopus Google Scholar). the embryonic of is to of early or the to the is in to the of these cells to Herein, we examine in cells in as to the in the in Cell a that GSK-3 stem was first by P. PubMed Scopus Google that of and the to a GSK-3 inhibition in the of and GSK-3 on cells have to by activation of the on the of GSK-3 However, on studies in cells derived from or and on studies in the is that are as J. S. Woodgett J. PubMed Scopus Google Scholar, B.W. S. Woodgett J.R. PubMed Scopus Google on the and have typically of growth is by cells in of the family that and and and of P. S. PubMed Scopus Google and in J. PubMed Scopus Google and PubMed Scopus Google Scholar). the in cells to that is inhibited by and has to by growth activation of the J. S. PubMed Scopus Google Scholar, PubMed Scopus Google has in the of the of including the that in the of as and P. J. PubMed Scopus Google Scholar, J. PubMed Scopus Google Scholar, J. J. Woodgett J. Cohen P. PubMed Scopus Google Scholar). J. J. Woodgett J. Cohen P. PubMed Scopus Google small molecule kinase to define this in of the growth and a of GSK-3 to of and in the of factors. The of inhibition of GSK-3 to was to was by by or or by the small molecule inhibitors. J. J. Woodgett J. Cohen P. PubMed Scopus Google that the of GSK-3 is to and growth in the of inhibition of the by and by of the and stem cells derived from P. J. PubMed Scopus Google have the of a that and growth to However, inhibition of GSK-3 is these studies have of this we the role of GSK-3 in of on of cells the an critical in during derived from cells of or or GSK-3 J. S. Woodgett J. PubMed Scopus Google Scholar, B.W. S. Woodgett J.R. PubMed Scopus Google in their to and of cells that and of in in the of in the and in an of in derived from cells a was to of of of to cardiomyocytes was by of or but by of of cells to the is the of the role of in inhibition of is PubMed Scopus Google Scholar, Sci. S. PubMed Scopus Google Scholar, S. Sci. S. PubMed Scopus Google Scholar). the as was activation of a by B.W. S. Woodgett J.R. PubMed Scopus Google Scholar). on the of and and on the of that the in the cells is of in cells to or but of and of was was a in in cells of and of B.W. S. Woodgett J.R. PubMed Scopus Google Scholar). data that the two are rate-limiting in the and are the in this is which of the two and is of GSK-3 in cells or in of as is in cells that or phosphorylation in in P. PubMed Scopus Google Scholar). these are by the of the and are in the and cells the first to to of GSK-3 in the of of including the the of of cardiomyocytes was that of the of was J. S. Woodgett J. PubMed Scopus Google Scholar). that which by studies of of and of a critical role in the of of cardiomyocytes to and J. S. Woodgett J. PubMed Scopus Google the of on has a of regulator of is which is in response to of P. S. PubMed Scopus Google Scholar). of by to its J. 2003; PubMed Scopus Google Scholar). phosphorylation has to and a phosphorylation and in the of P. S. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar). inhibition of GSK-3 of activation of and phosphorylation of and and P. S. PubMed Scopus Google Scholar, S. PubMed Scopus Google Scholar, J. PubMed Scopus Google Scholar, P. J. PubMed Scopus Google Scholar). or of was to a of a of the and that the of stem cells derived from S. PubMed Scopus Google Scholar, J. PubMed Scopus Google Scholar). of these are the of a of of cells as a the of the cells to J. PubMed Scopus Google and in in in mice to of J. Woodgett J.R. PubMed Scopus Google that of leads to embryonic in a of to is to the to in response to However, this appears to of the to that of which leads to the of the the of the majority of to and or of the of these and suggesting or by of as these critical the and or a that to to of from the in and J. S. Woodgett J. PubMed Scopus Google was to of in the of to appears to to a is the that to or and have the to to a to GSK-3 has that are of of of these and family as in the of these in during of these was which was to to S. P. PubMed Scopus Google Scholar, J. Google Scholar, S. J. PubMed Scopus Google Scholar). J. J. Cell PubMed Scopus Google to by GSK-3 on studies in of cells PubMed Scopus Google Scholar, J. PubMed Scopus Google Scholar, J.R. Scopus Google Scholar). studies the that these are in the in appears that the growth and their the that are to in the to the and that the in the of in the growth including growth growth and their in the in Cell PubMed Scopus Google Scholar). of activation of and appears to critical to the a of including and and or inhibition of appears to the to of the negative by leads to the of the and and embryonic appears to to in the of as of of family and as by the in the J. S. Woodgett J. PubMed Scopus Google Scholar). is and of the in cells and but in is to of as glycogen in the this in of the are in the two that of the to studies a role in the negative of in and that of to this this role of in is to cardiomyocytes is by the that inhibition of GSK-3 has to of the by stem cells PubMed Scopus Google was to and the studies in we of activation of in the J. Woodgett J.R. PubMed Scopus Google Scholar, J. S. Woodgett J. PubMed Scopus Google suggesting a role of in that is of of but appears to by of and to the of is of that is and in PubMed Scopus Google that of in of suggesting that this GSK-3 is to in and of or to a the in the and in the The of these are of has identified as a the of a of including and B.W. S. Woodgett J.R. Cell PubMed Scopus Google Scholar, S. B.W. Woodgett J.R. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, PubMed Scopus Google Scholar). over the of as inhibition of GSK-3 leads to of in this to S. S. J. Woodgett J.R. Sci. S. PubMed Scopus Google Scholar). the of and in the of and the inhibition of α to of is that a identified that GSK-3 in a to of its However, are to GSK-3-mediated of the and and as those in development. of the from which the GSK-3 has the of years PubMed Scopus Google Scholar). the as to leads to that is a GSK-3 inhibition of GSK-3 kinase and are in on is to the of these in of the past studies mice GSK-3 have identified a of of these kinases on a of in a variety of cells and The studies in cells and stem cells the first by P. PubMed Scopus Google that to GSK-3 play a role in is this GSK-3 the of the critical role of the GSK-3 in these cells a role the kinases as S. PubMed Scopus Google Scholar, J. PubMed Scopus Google Scholar). of is to the of during but the of GSK-3 inhibition in the to is that inhibition of have on of stem cells to the has on of the stem cells to in and this their to the of to of these cells in GSK-3 by of to a to to to the of GSK-3 inhibition on stem/progenitor or to to in these as as in cells and critical small molecule the isoforms, are of that The GSK-3 family of serine/threonine kinases was first identified as a negative regulator of glycogen synthase, the rate-limiting enzyme in glycogen synthesis (1Doble B.W. Woodgett J.R. J. Cell Sci. 2003; 116: 1175-1186Crossref PubMed Scopus (1744) Google Scholar, 2Frame S. Cohen P. Biochem. J. 2001; 359: 1-16Crossref PubMed Scopus (1266) Google Scholar). The family consists of two isoforms, α and β, which are 98% identical within their kinase domains but differ substantially in their N- and C-terminal sequences. Unlike most protein kinases, GSK-3 is typically active in unstimulated cells and is inhibited in response to a variety of inputs, including growth factors. Because GSK-3-mediated phosphorylation of substrates usually leads to inhibition of those substrates, the end result of growth factor-mediated inhibition of GSK-3 is typically functional activation of its downstream most attention has focused on the β-isoform of GSK-3. However, this bias appears to have arisen from two reports suggesting that mammalian was in to the in P. P. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar). However, in these the of of and was as we and to in of on studies in to play in embryonic protein kinase mice and in to glycogen in the B.W. S. Woodgett J.R. Cell PubMed Scopus Google Scholar). in J. Woodgett J.R. PubMed Scopus Google Scholar, J. S. Woodgett J. PubMed Scopus Google but of have in including glycogen synthase activation and glycogen S. B.W. Woodgett J.R. PubMed Scopus Google Scholar). of in the of the is to and the of in two of the in of the and of S. B.W. Woodgett J.R. PubMed Scopus Google Scholar). The of cells to and of these critical cells S. B.W. Woodgett J.R. PubMed Scopus Google Scholar). we on in this as we to and to of the isoforms, is to in that of the by in in or over the past years have GSK-3 as a critical regulator of in P. S. PubMed Scopus Google Scholar, P. J. PubMed Scopus Google Scholar, P. PubMed Scopus Google Scholar, J. PubMed Scopus Google Scholar, J. J. Woodgett J. Cohen P. PubMed Scopus Google Scholar). However, these studies typically have the small molecule which is GSK-3 and studies have cells or and from these studies a role the GSK-3 in including a role in the J. S. Woodgett J. PubMed Scopus Google Scholar, J. J. Woodgett J. Cohen P. PubMed Scopus Google Scholar, B.W. S. Woodgett J.R. PubMed Scopus Google Scholar). the embryonic of is to of early or the to the is in to the of these cells to Herein, we examine in cells in as to the in the in Cell a that GSK-3 stem was first by P. PubMed Scopus Google that of and the to a GSK-3 inhibition in the of and GSK-3 on cells have to by activation of the on the of GSK-3 However, on studies in cells derived from or and on studies in the is that are as J. S. Woodgett J. PubMed Scopus Google Scholar, B.W. S. Woodgett J.R. PubMed Scopus Google on the and have typically of growth is by cells in of the family that and and and of P. S. PubMed Scopus Google and in J. PubMed Scopus Google and PubMed Scopus Google Scholar). the in cells to that is inhibited by and has to by growth activation of the J. S. PubMed Scopus Google Scholar, PubMed Scopus Google has in the of the of including the that in the of as and P. J. PubMed Scopus Google Scholar, J. PubMed Scopus Google Scholar, J. J. Woodgett J. Cohen P. PubMed Scopus Google Scholar). J. J. Woodgett J. Cohen P. PubMed Scopus Google small molecule kinase to define this in of the growth and a of GSK-3 to of and in the of factors. The of inhibition of GSK-3 to was to was by by or or by the small molecule inhibitors. J. J. Woodgett J. Cohen P. PubMed Scopus Google that the of GSK-3 is to and growth in the of inhibition of the by and by of the and stem cells derived from P. J. PubMed Scopus Google have the of a that and growth to However, inhibition of GSK-3 is these studies have of this we the role of GSK-3 in of on of cells the an critical in during derived from cells of or or GSK-3 J. S. Woodgett J. PubMed Scopus Google Scholar, B.W. S. Woodgett J.R. PubMed Scopus Google in their to and of cells that and of in in the of in the and in an of in derived from cells a was to of of of to cardiomyocytes was by of or but by of of cells to the is the of the role of in inhibition of is PubMed Scopus Google Scholar, Sci. S. PubMed Scopus Google Scholar, S. Sci. S. PubMed Scopus Google Scholar). the as was activation of a by B.W. S. Woodgett J.R. PubMed Scopus Google Scholar). on the of and and on the of that the in the cells is of in cells to or but of and of was was a in in cells of and of B.W. S. Woodgett J.R. PubMed Scopus Google Scholar). data that the two are rate-limiting in the and are the in this is which of the two and is of GSK-3 in cells or in of as is in cells that or phosphorylation in in P. PubMed Scopus Google Scholar). these are by the of the and are in the and cells the first to to of GSK-3 in the of of including the the of of cardiomyocytes was that of the of was J. S. Woodgett J. PubMed Scopus Google Scholar). that which by studies of of and of a critical role in the of of cardiomyocytes to and J. S. Woodgett J. PubMed Scopus Google the of on has a of regulator of is which is in response to of P. S. PubMed Scopus Google Scholar). of by to its J. 2003; PubMed Scopus Google Scholar). phosphorylation has to and a phosphorylation and in the of P. S. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar). inhibition of GSK-3 of activation of and phosphorylation of and and P. S. PubMed Scopus Google Scholar, S. PubMed Scopus Google Scholar, J. PubMed Scopus Google Scholar, P. J. PubMed Scopus Google Scholar). or of was to a of a of the and that the of stem cells derived from S. PubMed Scopus Google Scholar, J. PubMed Scopus Google Scholar). of these are the of a of of cells as a the of the cells to J. PubMed Scopus Google Scholar). The that GSK-3 stem was first by P. PubMed Scopus Google that of and the to a GSK-3 inhibition in the of and GSK-3 on cells have to by activation of the on the of GSK-3 However, on studies in cells derived from or and on studies in the is that are as J. S. Woodgett J. PubMed Scopus Google Scholar, B.W. S. Woodgett J.R. PubMed Scopus Google Scholar). on the and have typically of growth is by cells in of the family that and and and of P. S. PubMed Scopus Google and in J. PubMed Scopus Google and PubMed Scopus Google Scholar). the in cells to that is inhibited by and has to by growth activation of the J. S. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar). has in the of the of including the that in the of as and P. J. PubMed Scopus Google Scholar, J. PubMed Scopus Google Scholar, J. J. Woodgett J. Cohen P. PubMed Scopus Google Scholar). J. J. Woodgett J. Cohen P. PubMed Scopus Google small molecule kinase to define this in of the growth and a of GSK-3 to of and in the of factors. The of inhibition of GSK-3 to was to was by by or or by the small molecule inhibitors. J. J. Woodgett J. Cohen P. PubMed Scopus Google that the of GSK-3 is to and growth in the of inhibition of the by and by of the and stem cells derived from P. J. PubMed Scopus Google have the of a that and growth to However, inhibition of GSK-3 is Because these studies have of this we the role of GSK-3 in of on of cells the an critical in during derived from cells of or or GSK-3 J. S. Woodgett J. PubMed Scopus Google Scholar, B.W. S. Woodgett J.R. PubMed Scopus Google Scholar). in their to and of cells that and of in in the of in the and in an of in derived from cells a was to of of of to cardiomyocytes was by of or but by of GSK-3. The of cells to the is the of the role of in inhibition of is PubMed Scopus Google Scholar, Sci. S. PubMed Scopus Google Scholar, S. Sci. S. PubMed Scopus Google Scholar). the as was activation of a by B.W. S. Woodgett J.R. PubMed Scopus Google Scholar). on the of and and on the of that the in the cells is of in cells to or but of and of was was a in in cells of and of B.W. S. Woodgett J.R. PubMed Scopus Google Scholar). data that the two are rate-limiting in the and are the in this is which of the two and is of GSK-3 in cells or in of as is in cells that or phosphorylation in in P. PubMed Scopus Google Scholar). these are by the of the and are in the and cells the first to to of GSK-3 in the of of including the the of of cardiomyocytes was that of the of was J. S. Woodgett J. PubMed Scopus Google Scholar). that which by studies of of and of a critical role in the of of cardiomyocytes to and J. S. Woodgett J. PubMed Scopus Google Scholar). the of on has a of regulator of is which is in response to of P. S. PubMed Scopus Google Scholar). of by to its J. 2003; PubMed Scopus Google Scholar). phosphorylation has to and a phosphorylation and in the of P. S. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar). inhibition of GSK-3 of activation of and phosphorylation of and and P. S. PubMed Scopus Google Scholar, S. PubMed Scopus Google Scholar, J. PubMed Scopus Google Scholar, P. J. PubMed Scopus Google Scholar). or of was to a of a of the and that the of stem cells derived from S. PubMed Scopus Google Scholar, J. PubMed Scopus Google Scholar). of these are the of a of of cells as a the of the cells to J. PubMed Scopus Google Scholar). and in in in mice to of J. Woodgett J.R. PubMed Scopus Google that of leads to embryonic in a of to is to the to in response to However, this appears to of the to that of which leads to the of the the of the majority of to and or of the of these and suggesting or by of as these critical the and or a that to to of from the in and J. S. Woodgett J. PubMed Scopus Google was to of in the of to appears to to a is the that to or and have the to to a to GSK-3 has that are of of of these and family as in the of these in during of these was which was to to S. P. PubMed Scopus Google Scholar, J. Google Scholar, S. J. PubMed Scopus Google Scholar). J. J. Cell PubMed Scopus Google to by GSK-3 on studies in of cells PubMed Scopus Google Scholar, J. PubMed Scopus Google Scholar, J.R. Scopus Google Scholar). studies the that these are in the in appears that the growth and their the that are to in the to the and that the in the studies a role in the negative of in and that of to this this role of in is to cardiomyocytes is by the that inhibition of GSK-3 has to of the by stem cells PubMed Scopus Google was to and the studies in we of activation of in the J. Woodgett J.R. PubMed Scopus Google Scholar, J. S. Woodgett J. PubMed Scopus Google suggesting a role of in that is of of but appears to by of and to the of is of that is and in PubMed Scopus Google that of in of suggesting that this GSK-3 is to in and of or to a the in the and in the The of these are in in mice to of J. Woodgett J.R. PubMed Scopus Google that of leads to embryonic in a of to is to the to in response to However, this appears to of the to that of which leads to the of the the of the majority of to and or of the of these and suggesting or by of as these critical the and or a that to to of from the in and J. S. Woodgett J. PubMed Scopus Google Scholar). was to of in the of to appears to to a is the that to or and have However, the to to a to GSK-3 has that are of of of these and family as in the of these in during of these was which was to to S. P. PubMed Scopus Google Scholar, J. Google Scholar, S. J. PubMed Scopus Google Scholar). J. J. Cell PubMed Scopus Google to by GSK-3 on studies in of cells PubMed Scopus Google Scholar, J. PubMed Scopus Google Scholar, J.R. Scopus Google Scholar). studies the that these are in the in appears that the growth and their the that are to in the to the and that the in the studies a role in the negative of in and that of to this this role of in is to cardiomyocytes is by the that inhibition of GSK-3 has to of the by stem cells PubMed Scopus Google was to and the studies in we of activation of in the J. Woodgett J.R. PubMed Scopus Google Scholar, J. S. Woodgett J. PubMed Scopus Google suggesting a role of in that is of of but appears to by of and to the of is of that is and in PubMed Scopus Google that of in of suggesting that this GSK-3 is to in and of or to a the in the and in the The of these are of has identified as a the of a of including and B.W. S. Woodgett J.R. Cell PubMed Scopus Google Scholar, S. B.W. Woodgett J.R. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, PubMed Scopus Google Scholar). over the of as inhibition of GSK-3 leads to of in this to S. S. J. Woodgett J.R. Sci. S. PubMed Scopus Google Scholar). the of and in the of and the inhibition of α to of is that a identified that GSK-3 in a to of its However, are to GSK-3-mediated of the and and as those in development. of the from which the GSK-3 has the of years PubMed Scopus Google Scholar). the as to leads to that is a GSK-3 inhibition of GSK-3 kinase and are in on is to the of these in of GSK-3 has identified as a the of a of including and B.W. S. Woodgett J.R. Cell PubMed Scopus Google Scholar, S. B.W. Woodgett J.R. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, PubMed Scopus Google Scholar). over the of as inhibition of GSK-3 leads to of in this to S. S. J. Woodgett J.R. Sci. S. PubMed Scopus Google Scholar). the of and in the of and the inhibition of α to of is that a identified that GSK-3 in a to of its However, are to GSK-3-mediated of the and and as those in development. of the from which the GSK-3 has the of years PubMed Scopus Google Scholar). the as to leads to that is a GSK-3 inhibition of GSK-3 kinase and are in on is to the of these in of the past studies mice GSK-3 have identified a of of these kinases on a of in a variety of cells and The studies in cells and stem cells the first by P. PubMed Scopus Google that to GSK-3 play a role in is this GSK-3 the of the critical role of the GSK-3 in these cells a role the kinases as S. PubMed Scopus Google Scholar, J. PubMed Scopus Google Scholar). of is to the of during but the of GSK-3 inhibition in the to is that inhibition of have on of stem cells to the has on of the stem cells to in and this their to the of to of these cells in GSK-3 by of to a to to to the of GSK-3 inhibition on stem/progenitor or to to in these as as in cells and critical small molecule the isoforms, are of that the past studies mice GSK-3 have identified a of of these kinases on a of in a variety of cells and The studies in cells and stem cells the first by P. PubMed Scopus Google that to GSK-3 play a role in is this GSK-3 the of the critical role of the GSK-3 in these cells a role the kinases as S. PubMed Scopus Google Scholar, J. PubMed Scopus Google Scholar). of is to the of during but the of GSK-3 inhibition in the to is that inhibition of have on of stem cells to the has on of the stem cells to in and this their to the of to of these cells in GSK-3 by of to a to to to the of GSK-3 inhibition on stem/progenitor or to to in these as as in cells and critical small molecule the isoforms, are of that of the

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