Labour's Tristram Hunt is quitting as an MP to become the director of London's Victoria and Albert Museum, triggering a by-election.
The former Shadow Education Secretary's Stoke-on-Trent Central seat is among constituencies set to be abolished under new boundary proposals.
But his move follows the resignation of Jamie Reed as MP for Copeland in Cumbria and other centrist senior party figures no longer being available to serve in Jeremy Corbyn's Shadow Cabinet such as Yvette Cooper and Hilary Benn, who are pursuing their Commons careers chairing Commons committees.
Mr Hunt, once talked about as a potential future Labour leader, confirmed the news to the BBC but an announcement is due later.
He said: "It's about the opportunity to have one of the greatest museum jobs in the world."
In a letter to local party members, he wrote: "As I enter a new role as a public servant, I will be leaving partisan politics behind me and will work impartially as a museum director.
"I am sorry to put you, the party and the people of Stoke-on-Trent through a by-election.
"I have no desire to rock the boat now and anyone who interprets my decision to leave in that way is just plain wrong."
Mr Hunt said serving in Parliament had been "both deeply rewarding and intensely frustrating" and told of the "harrowing effects of poverty and inequality" he had seen during his work as an MP.
He added: "The frustration, of course, came with the inability to address those factors and implement our policy programme following our defeat in 2015 - and, more broadly, about how the Labour Party should respond to the social, cultural and economic forces which have rocked mainstream social democratic and socialist parties from India to Greece to America.
"There were very few jobs that would have convinced me to stand down as MP for Stoke-on-Trent Central, but the post of director of the V&A - the world's greatest museum of art, design and performance - is just that."
A spokesman for Labour leader Jeremy Corbyn said: "Jeremy would like to thank Tristram Hunt for his service to the people of Stoke-on-Trent Central and to the Labour Party. Jeremy wishes him well in his future pursuits at the V&A."
Culture Secretary Karen Bradley said: "I congratulate Tristram Hunt in being named Director of the V&A. He has a wealth of experience as a historian and a great passion for arts and culture that will serve him very well in this role.
"The V&A is one of the world's leading art institutions and I am sure that Tristram will build on its fantastic reputation further.
"I look forward to working alongside him."
Mr Hunt's V&A appointment was signed off by Prime Minister Theresa May and Culture Secretary Karen Bradley.
The V&A said the MP had been at the forefront of political, cultural and public life for the last decade.
Chairman Nicholas Coleridge said: "He has a highly compelling mixture of experience across public life, the arts, history, education and academia, and knows our collections well from his writing and broadcasting. In addition, he is an informed and articulate leader and communicator on numerous facets of culture, both historic and contemporary, and I greatly look forward to working with him at the V&A."
Mr Hunt said: "I have loved the V&A since I was a boy, and today it is a global leader in its unrivalled collections, special exhibitions, academic research and visitor experience.
"It is a moment of transformation and renewal for the V&A, with the upcoming opening of the new Exhibition Road entrance, and new sites and galleries in Dundee, China and Stratford. I am particularly pleased that, through the V&A ownership of the Wedgwood Collection, my passion for education in Stoke-on-Trent can continue."
Deputy Labour leader Tom Watson said he was "disappointed" Mr Hunt was quitting.
He said: "I am disappointed to see a talented MP like Tristram step down. His departure will be keenly felt by Parliament and by the Labour Party but I know he will continue to champion Stoke-on-Trent's proud industrial heritage in his new role at the Victoria and Albert Museum.
"The Labour Party will move swiftly to ensure Stoke-on-Trent Central continues to be represented by a strong and capable Labour MP."
Ms Bradley said: "I congratulate Tristram Hunt in being named director of the V&A. He has a wealth of experience as a historian and a great passion for arts and culture that will serve him very well in this role.
"The V&A is one of the world's leading art institutions and I am sure that Tristram will build on its fantastic reputation further. I look forward to working alongside him."
Mr Hunt is the second centrist Labour MP in a matter of weeks to quit Parliament for a job outside politics, following Jamie Reed, who announced last month he was standing down as MP for Copeland to take up a post at the Sellafield nuclear plant.
Their decisions to quit politics are being seen by Westminster-watchers as a sign of Labour's remaining Blairites losing hope of reversing the party's shift to the left.
Mr Hunt's departure sets up another potentially awkward by-election for Mr Corbyn, in a traditionally safe Labour seat where Ukip made a strong showing in the last general election. Stoke voted Leave by 65.7% in last year's EU referendum - one of the biggest Brexit votes in the country.
Labour has held Stoke-on-Trent Central since the constituency's creation in 1950, with a vote-share of 66% and majority of 49.5%, making it one of the party's safest strongholds in 1997.
But its majority has since fallen to 17%, with Ukip surging by 18 points to take second place in 2015, and the febrile state of UK politics means Labour cannot be as confident of holding onto the seat as it has been in the past.
There was immediate speculation that Ukip's new leader Paul Nuttall may stand in the by-election in a bid to make good on his promise to replace Labour as the party of choice for working class communities in the Midlands and North of England.
Former Ukip leader Nigel Farage said: "Tristram Hunt's resignation from Stoke will be followed by many others. Labour is doomed."
Liberal Democrat president Baroness (Sal) Brinton said Mr Hunt's resignation was "a sign of how Labour are ripping themselves apart".
"What is worrying is when first Jamie Reed and now Tristram Hunt decide they can achieve more positive change outside, rather than inside Parliament," said Lady Brinton.
"These decent, civic-minded people got into politics to make a difference and we are poorer now for Tristram leaving Westminster."
Lib Dems took second place in Stoke Central in the 2005 and 2010 elections, before slumping to fifth in 2015, when Mr Hunt secured a 5,179-vote majority with 39.3%, over Ukip's 22.7% and Conservatives on 22.5%.
Mr Hunt refused to serve in the shadow cabinet following Mr Corbyn's shock leadership win in September 2015.
He was among leading Labour moderates whose seats are facing significant boundary changes. It would have left him vulnerable to de-selection attempts by hardline supporters of Mr Corbyn.
Ukip chairman Paul Oakden said the party will be "fighting hard" to win the seat and will confirm its candidate later this month.
He said: "The resignation of Tristram Hunt MP highlights the brighter future that many in the Labour Party feel they have away from Jeremy Corbyn and his brand of politics.
"We have no doubt that the example set by Mr Hunt will be one that many voters in Stoke-on-Trent will consider following in the upcoming by-election, where Ukip will be fighting hard to offer local people the committed representation they both need and deserve.
"Ukip will confirm the selection of its candidate on Saturday 21st January."
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